Editing Endoplasmic reticulum

{{Short description|Cell organelle that processes proteins}}
{{pp-move}}
[[File:Blausen 0350 EndoplasmicReticulum.png|thumb|300px|3D rendering of endoplasmic reticulum]]
{{Organelle diagram}}

The '''endoplasmic reticulum''' ('''ER''') is a part of a transportation system of the [[eukaryote|eukaryotic cell]], and has many other important functions such as [[protein folding]]. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little net". It is a type of [[organelle]] made up of two subunits – '''rough endoplasmic reticulum''' ('''RER'''), and '''smooth endoplasmic reticulum''' ('''SER'''). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as [[cisterna]]e (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer [[nuclear membrane]]. The endoplasmic reticulum is not found in [[red blood cell]]s, or [[spermatozoa]].

There are two types of ER that share many of the same [[protein]]s and engage in certain common activities such as the synthesis of certain [[lipid]]s and [[cholesterol]]. Different types of [[Cell (biology)|cells]] contain different ratios of the two types of ER depending on the activities of the cell. RER is found mainly toward the nucleus of the cell and SER towards the cell membrane or plasma membrane of cell.

The outer ([[cytosol]]ic) face of the RER is studded with [[ribosome]]s that are the sites of [[protein synthesis]]. The RER is especially prominent in cells such as [[hepatocyte]]s. The SER lacks ribosomes and functions in [[lipid]] synthesis but not [[metabolism]], the production of [[steroid hormone]]s, and [[detoxification]].<ref name="BSCB-2015">{{cite web|title=Endoplasmic Reticulum (Rough and Smooth)|url=http://bscb.org/learning-resources/softcell-e-learning/endoplasmic-reticulum-rough-and-smooth/|access-date=21 November 2015|url-status=live|publisher=  British Society of Cell Biology|archive-url=https://web.archive.org/web/20151124032610/http://bscb.org/learning-resources/softcell-e-learning/endoplasmic-reticulum-rough-and-smooth/|archive-date=24 November 2015}}</ref> The SER is especially abundant in mammalian [[liver]] and [[gonad]] cells.

The ER was observed by [[light microscopy]] by Charles Garnier in 1897, who coined the term ''ergastoplasm''.<ref>{{cite journal |last1=Garnier |first1=C. |year=1897 |title=Les filaments basaux des cellules glandulaires. Note préliminaire |journal=Bibliographie Anatomique |volume=5 |pages=278–289 |oclc=493441682 |url=https://www.biodiversitylibrary.org/page/902759 }}</ref><ref name="Buvat-1963">{{cite book |doi=10.1016/S0074-7696(08)60021-2 |chapter=Electron Microscopy of Plant Protoplasm |title=International Review of Cytology Volume 14 |year=1963 |last1=Buvat |first1=R. |volume=14 |pages=41–155 |pmid=14283576 |isbn=978-0-12-364314-8 }}</ref> The lacy membranes of the endoplasmic reticulum were first seen by [[electron microscopy]] in 1945 by [[Keith R. Porter]], [[Albert Claude]], and Ernest F. Fullam.<ref name="Porter-1945">{{cite journal | vauthors = Porter KR, Claude A, Fullam EF | title = A study of tissue culture cells by electron microscopy: methods and preliminary observations | journal = The Journal of Experimental Medicine | volume = 81 | issue = 3 | pages = 233–46 | date = March 1945 | pmid = 19871454 | pmc = 2135493 | doi = 10.1084/jem.81.3.233 }}</ref>

== Structure ==
[[File:Nucleus ER golgi.svg|thumb|300px|'''1'''&nbsp;[[Cell nucleus|Nucleus]]{{nbsp|2}}
'''2'''&nbsp;[[Nuclear pore]]{{nbsp|2}}
'''3'''&nbsp;Rough endoplasmic reticulum (RER){{nbsp|2}}
'''4'''&nbsp;Smooth endoplasmic reticulum (SER){{nbsp|2}}
'''5'''&nbsp;[[Ribosome]] on the rough ER{{nbsp|2}}
'''6'''&nbsp;[[Protein]]s that are transported{{nbsp|2}}
'''7'''&nbsp;Transport [[Vesicle (biology)|vesicle]]{{nbsp|2}}
'''8'''&nbsp;[[Golgi apparatus]]{{nbsp|2}}
'''9'''&nbsp;Cis face of the Golgi apparatus{{nbsp|2}}
'''10'''&nbsp;Trans face of the Golgi apparatus{{nbsp|2}}
'''11'''&nbsp;Cisternae of the Golgi apparatus]]

The general structure of the endoplasmic reticulum is a network of membranes called [[cisterna]]e. These sac-like structures are held together by the [[cytoskeleton]]. The [[phospholipid membrane]] encloses the cisternal space (or lumen), which is continuous with the [[perinuclear space]] but separate from the [[cytosol]]. The functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function.  The quantity of both rough and smooth endoplasmic reticulum in a cell can slowly interchange from one type to the other, depending on the changing metabolic activities of the cell.  Transformation can include embedding of new proteins in membrane as well as structural changes.  Changes in protein content may occur without noticeable structural changes.<ref name="Alberts-2002">{{cite book | last1 = Alberts | first1 = Bruce | last2 = Johnson | first2 = Alexander | last3 = Lewis | first3 = Julian | last4 = Raff | first4 = Martin | last5 = Roberts | first5 = Keith | last6 = Walter | first6 = Peter | name-list-style = vanc | title = Molecular biology of the cell | date = 2002 | publisher = Garland Science | location = New York | isbn = 978-0-8153-3218-3 | edition = 4th | url = https://www.ncbi.nlm.nih.gov/books/NBK26841/ | url-status = live | archive-url = https://web.archive.org/web/20171003052046/https://www.ncbi.nlm.nih.gov/books/NBK26841/ | archive-date = 2017-10-03 }}</ref><ref>{{cite book|last1=Cooper|first1=Geoffrey M.|name-list-style=vanc|title=The cell: a molecular approach|date=2000|publisher=ASM Press|location=Washington (DC)|isbn=978-0-87893-106-4|edition=2nd|url=https://archive.org/details/cell00geof|url-access=registration}}</ref>

===Rough endoplasmic reticulum===
[[File: Protein translation.gif|thumb|300px|A 2-minute animation showing how a protein destined for the [[secretory pathway]] is synthesized and secreted into the rough endoplasmic reticulum, which appears at the upper right approximately halfway through the animation]]
The surface of the rough endoplasmic reticulum (often abbreviated ''RER'' or ''rough ER''; also called ''granular endoplasmic reticulum'') is studded with protein-manufacturing [[ribosome]]s giving it a "rough" appearance (hence its name).<ref>{{cite web|title=reticulum|url=http://medical-dictionary.thefreedictionary.com/reticulum|website=The Free Dictionary}}</ref> The binding site of the ribosome on the rough endoplasmic reticulum is the [[translocon]].<ref>{{cite journal | vauthors = Görlich D, Prehn S, Hartmann E, Kalies KU, Rapoport TA | title = A mammalian homolog of SEC61p and SECYp is associated with ribosomes and nascent polypeptides during translocation | journal = Cell | volume = 71 | issue = 3 | pages = 489–503 | date = October 1992 | pmid = 1423609 | doi = 10.1016/0092-8674(92)90517-G | s2cid = 19078317 }}</ref> However, the ribosomes are not a stable part of this organelle's structure as they are constantly being bound and released from the membrane. A ribosome only binds to the RER once a specific protein-nucleic acid complex forms in the cytosol.  This special complex forms when a free ribosome begins [[translation (biology)|translating]] the [[mRNA]] of a protein destined for the [[secretory pathway]].<ref name="Lodish-2003">{{cite book |last=Lodish |first=Harvey |name-list-style=vanc |year=2003 |title=Molecular Cell Biology |edition=5th |publisher=W. H. Freeman |pages=[https://archive.org/details/molecularcellbio00harv/page/659 659–666] |isbn=978-0-7167-4366-8 |display-authors=etal |url-access=registration |url=https://archive.org/details/molecularcellbio00harv/page/659 }}</ref> The first 5–30 [[amino acid]]s polymerized encode a [[signal peptide]], a molecular message that is recognized and bound by a [[signal recognition particle]] (SRP). Translation pauses and the ribosome complex binds to the RER [[translocon]] where translation continues with the [[ribosome-nascent chain complex|nascent]] (new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signal [[peptidase]]), which removes the signal peptide. Ribosomes at this point may be released back into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons.<ref name="Seiser-2000">{{cite journal | vauthors = Seiser RM, Nicchitta CV | title = The fate of membrane-bound ribosomes following the termination of protein synthesis | journal = The Journal of Biological Chemistry | volume = 275 | issue = 43 | pages = 33820–7 | date = October 2000 | pmid = 10931837 | doi = 10.1074/jbc.M004462200 | doi-access = free }}</ref>

The membrane of the rough endoplasmic reticulum is in the form of large double-membrane sheets that are located near, and continuous with, the outer layer of the [[nuclear envelope]].<ref name="Shibata-2006">{{cite journal | vauthors = Shibata Y, Voeltz GK, Rapoport TA | title = Rough sheets and smooth tubules | journal = Cell | volume = 126 | issue = 3 | pages = 435–9 | date = August 2006 | pmid = 16901774 | doi = 10.1016/j.cell.2006.07.019 | s2cid = 16107069 | doi-access = free }}</ref> The double membrane sheets are stacked and connected through several right- or left-handed helical ramps, the "Terasaki ramps", giving rise to a structure resembling  a [[parking garage]].<ref name="Terasaki-2013">{{cite journal | vauthors = Terasaki M, Shemesh T, Kasthuri N, Klemm RW, Schalek R, Hayworth KJ, Hand AR, Yankova M, Huber G, Lichtman JW, Rapoport TA, Kozlov MM | title = Stacked endoplasmic reticulum sheets are connected by helicoidal membrane motifs | journal = Cell | volume = 154 | issue = 2 | pages = 285–96 | date = July 2013 | pmid = 23870120 | pmc = 3767119 | doi = 10.1016/j.cell.2013.06.031 }}</ref><ref name="Guven-2014">{{cite journal | vauthors = Guven J, Huber G, Valencia DM | title = Terasaki spiral ramps in the rough endoplasmic reticulum | journal = Physical Review Letters | volume = 113 | issue = 18 | pages = 188101 | date = October 2014 | pmid = 25396396 | doi = 10.1103/PhysRevLett.113.188101 | bibcode = 2014PhRvL.113r8101G }}</ref> Although there is no continuous membrane between the endoplasmic reticulum and the [[Golgi apparatus]], membrane-bound [[Vesicle (biology and chemistry)#Transport vesicle|transport vesicles]] shuttle proteins between these two compartments.<ref>Endoplasmic reticulum. (n.d.). [[McGraw-Hill Encyclopedia of Science and Technology]]. Retrieved September 13, 2006, from Answers.com Web site: {{cite web |url=http://www.answers.com/topic/endoplasmic-reticulum |title=Answers - the Most Trusted Place for Answering Life's Questions |website=[[Answers.com]] |access-date=2006-09-13 |url-status=live |archive-url=https://web.archive.org/web/20061116131259/http://www.answers.com/topic/endoplasmic-reticulum |archive-date=2006-11-16 }}</ref> Vesicles are surrounded by [[Vesicular transport adaptor protein|coating proteins]] called COPI and COPII. [[COPII]] targets vesicles to the Golgi apparatus and [[COPI]] marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the [[Golgi complex]] to [[protein targeting|target new proteins]] to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called [[membrane contact site]]s, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules.<ref>{{cite journal | vauthors = Levine T | title = Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions | journal = Trends in Cell Biology | volume = 14 | issue = 9 | pages = 483–90 | date = September 2004 | pmid = 15350976 | doi = 10.1016/j.tcb.2004.07.017 }}</ref><ref>{{cite journal | vauthors = Levine T, Loewen C | title = Inter-organelle membrane contact sites: through a glass, darkly | journal = Current Opinion in Cell Biology | volume = 18 | issue = 4 | pages = 371–8 | date = August 2006 | pmid = 16806880 | doi = 10.1016/j.ceb.2006.06.011 }}</ref>

The rough endoplasmic reticulum is key in multiple functions:
* Manufacture of [[Lysosome|lysosomal]] enzymes with a [[mannose-6-phosphate]] marker added in the ''cis''-Golgi network.<ref>{{Cite journal |last1=Čaval |first1=Tomislav |last2=Zhu |first2=Jing |last3=Tian |first3=Weihua |last4=Remmelzwaal |first4=Sanne |last5=Yang |first5=Zhang |last6=Clausen |first6=Henrik |last7=Heck |first7=Albert J. R. |date=2019-01-01 |title=Targeted Analysis of Lysosomal Directed Proteins and Their Sites of Mannose-6-phosphate Modification*[S] |journal=Molecular & Cellular Proteomics |volume=18 |issue=1 |pages=16–27 |doi=10.1074/mcp.RA118.000967 |doi-access=free |pmid=30237200 |issn=1535-9476|pmc=6317476 }}</ref>
* Manufacture of [[Secretion|secreted]] proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving [[clathrin]] and paired basic amino acids in the [[signal peptide]].
* [[Integral membrane proteins]] that stay embedded in the membrane as vesicles exit and bind to new membranes. [[Rab (G-protein)|Rab]] proteins are key in targeting the membrane; [[SNAP-25|SNAP]] and [[SNARE]] proteins are key in the fusion event.
* Initial [[glycosylation]] as assembly continues. This is N-linked (O-linking occurs in the Golgi).
** N-linked glycosylation: If the protein is properly folded, [[oligosaccharyltransferase]] recognizes the AA sequence [[Asparagine|N]]X[[serine|S]] or [[Asparagine|N]]X[[threonine|T]] (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-''N''-acetylglucosamine, 9-branching [[mannose]], and 3-[[glucose]] at the end) to the side-chain [[nitrogen]] of Asn.

The RER has ribosomes while the SER does not.

===Smooth endoplasmic reticulum===
[[File:0313 Endoplasmic Reticulum c labeled.png|thumb|left|250px|Electron micrograph showing smooth ER (arrow) in mouse tissue, at 110,510× magnification]]

In most cells the smooth endoplasmic reticulum (abbreviated '''SER''') is scarce. Instead there are areas where the ER is partly smooth and partly rough, this area is called the transitional ER. The transitional ER gets its name because it contains ER exit sites. These are areas where the transport vesicles which contain lipids and proteins made in the ER, detach from the ER and start moving to the [[Golgi apparatus]]. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions.<ref name="Alberts-2002" /> It synthesizes [[lipids]], [[phospholipids]],<ref>{{cite journal |last1=Kannan |first1=Muthukumar |last2=Lahiri |first2=Sujoy |last3=Liu |first3=Li-Ka |last4=Choudhary |first4=Vineet |last5=Prinz |first5=William A. |title=Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER |journal=Journal of Lipid Research |date=March 2017 |volume=58 |issue=3 |pages=553–562 |doi=10.1194/jlr.M072959  |doi-access=free |pmid=28119445 |pmc=5335585 }}</ref><ref>{{cite journal |last1=Kannan |first1=Muthukumar |last2=Riekhof |first2=Wayne R. |last3=Voelker |first3=Dennis R. |title=Transport of Phosphatidylserine from the Endoplasmic Reticulum to the Site of Phosphatidylserine Decarboxylase2 in Yeast: Phosphatidylserine Transport to the Locus of Psd2p |journal=Traffic |date=February 2015 |volume=16 |issue=2 |pages=123–134 |doi=10.1111/tra.12236 |pmid=25355612 |s2cid=34302 |doi-access= }}</ref><ref>{{cite journal |last1=Friedman |first1=Jonathan R. |last2=Kannan |first2=Muthukumar |last3=Toulmay |first3=Alexandre |last4=Jan |first4=Calvin H. |last5=Weissman |first5=Jonathan S. |last6=Prinz |first6=William A. |last7=Nunnari |first7=Jodi |title=Lipid Homeostasis Is Maintained by Dual Targeting of the Mitochondrial PE Biosynthesis Enzyme to the ER |journal=Developmental Cell |date=January 2018 |volume=44 |issue=2 |pages=261–270.e6 |doi=10.1016/j.devcel.2017.11.023 |pmid=29290583 |pmc=5975648 }}</ref> and [[steroids]]. Cells which secrete these products, such as those in the [[testes]], [[ovaries]], and [[sebaceous gland]]s have an abundance of smooth endoplasmic reticulum.<ref>{{cite news|title=Functions of Smooth ER|publisher=University of Minnesota Duluth}}<!--|access-date=16 December 2012--></ref> It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, attachment of receptors on cell membrane proteins, and [[steroid metabolism]].<ref>{{cite journal | vauthors = Maxfield FR, Wüstner D | title = Intracellular cholesterol transport | journal = The Journal of Clinical Investigation | volume = 110 | issue = 7 | pages = 891–8 | date = October 2002 | pmid = 12370264 | pmc = 151159 | doi = 10.1172/JCI16500 }}</ref> In muscle cells, it regulates [[Calcium in biology|calcium ion]] concentration. Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmic reticulum also contains the enzyme [[glucose-6-phosphatase]], which converts [[glucose-6-phosphate]] to glucose, a step in [[gluconeogenesis]]. It is connected to the [[nuclear envelope]] and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance.<ref name="Shibata-2006" /> In some cells, there are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to be devoted to the action or storage of key enzymes and the products of these enzymes.{{cn|date=December 2023}}

==== Sarcoplasmic reticulum ====
[[File:Blausen 0801 SkeletalMuscle.png|thumb|left|250px|[[Skeletal muscle]] fiber, with sarcoplasmic reticulum colored in blue]]
{{main|Sarcoplasmic reticulum}}
{{See also |Calcium-induced calcium release}}

The sarcoplasmic reticulum (SR), from the Greek σάρξ ''sarx'' ("flesh"), is smooth ER found in [[muscle cell]]s.  The only structural difference between this organelle and the smooth endoplasmic reticulum is the composition of proteins they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while the sarcoplasmic reticulum stores calcium ions and pumps them out into the sarcoplasm when the muscle fiber is stimulated.<ref name="Toyoshima-2000">{{cite journal | vauthors = Toyoshima C, Nakasako M, Nomura H, Ogawa H | title = Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution | journal = Nature | volume = 405 | issue = 6787 | pages = 647–55 | date = June 2000 | pmid = 10864315 | doi = 10.1038/35015017 | bibcode = 2000Natur.405..647T | s2cid = 4316039 }}</ref><ref>{{cite book | first = Steven R | last = Goodman | name-list-style = vanc | title = Medical Cell Biology | edition = 3rd|publisher=Academic Press|pages=69|url=https://books.google.com/books?id=tRbCHk9easQC&q=smooth+er+stores+calcium+ions+muscle+cells&pg=PA69 | isbn = 9780080919317 | date = 2007-11-26 }}</ref> After their release from the sarcoplasmic reticulum, calcium ions interact with contractile proteins that utilize ATP to shorten the muscle fiber. The sarcoplasmic reticulum plays a major role in [[excitation-contraction coupling]].<ref>{{cite book |title = Fundamentals of Anatomy and Physiology |first1 = Frederick |last1 = Martini |first2 = Judi |last2 = Nath |first3 = Edwin |last3 = Bartholomew | name-list-style = vanc |edition = 10th |isbn = 978-0321909077 |year = 2014|publisher = Pearson }}</ref>

==Functions==
The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called [[cisterna]]e and the transport of synthesized proteins in [[Golgi apparatus#Vesicular transport|vesicles]] to the [[Golgi apparatus]]. Rough endoplasmic reticulum is also involved in protein synthesis. Correct folding of newly made proteins is made possible by several endoplasmic reticulum [[Chaperone (protein)|chaperone]] proteins, including [[protein disulfide isomerase]] (PDI), ERp29, the [[Hsp70]] family member [[Binding immunoglobulin protein|BiP/Grp78]], [[calnexin]], [[calreticulin]], and the peptidylprolyl isomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus – unfolded proteins cause an [[unfolded protein response]] as a stress response in the ER. Disturbances in [[redox]] regulation, calcium regulation, glucose deprivation, and viral infection<ref>{{cite journal | vauthors = Xu C, Bailly-Maitre B, Reed JC | title = Endoplasmic reticulum stress: cell life and death decisions | journal = The Journal of Clinical Investigation | volume = 115 | issue = 10 | pages = 2656–64 | date = October 2005 | pmid = 16200199 | pmc = 1236697 | doi = 10.1172/JCI26373 }}</ref> or the over-expression of proteins<ref name="Kober-2012">{{cite journal | vauthors = Kober L, Zehe C, Bode J | title = Development of a novel ER stress based selection system for the isolation of highly productive clones | journal = Biotechnology and Bioengineering | volume = 109 | issue = 10 | pages = 2599–611 | date = October 2012 | pmid = 22510960 | doi = 10.1002/bit.24527 | s2cid = 25858120 }}</ref> can lead to [[XBP1#Endoplasmic reticulum stress response|endoplasmic reticulum stress response]] (ER stress), a state in which the folding of proteins slows, leading to an increase in [[Unfolded protein response|unfolded proteins]]. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.<ref>{{cite journal | vauthors = Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS | title = Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes | journal = Science | volume = 306 | issue = 5695 | pages = 457–61 | date = October 2004 | pmid = 15486293 | doi = 10.1126/science.1103160 | bibcode = 2004Sci...306..457O | s2cid = 22517395 }}</ref>

===Protein transport===
Secretory proteins, mostly [[glycoproteins]], are moved across the endoplasmic reticulum membrane. Proteins that are transported by the endoplasmic reticulum throughout the cell are marked with an address tag called a [[signal peptide|signal sequence]]. The N-terminus (one end) of a [[polypeptide]] chain (i.e., a protein) contains a few [[amino acid]]s that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the [[translocon]], a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport [[vesicle (biology)|vesicle]]s and moved along the [[cytoskeleton]] toward their destination. In human fibroblasts, the ER is always co-distributed with microtubules and the depolymerisation of the latter cause its co-aggregation with mitochondria, which are also associated with the ER.<ref>{{cite journal | vauthors = Soltys BJ, Gupta RS | title = Interrelationships of endoplasmic reticulum, mitochondria, intermediate filaments, and microtubules--a quadruple fluorescence labeling study | journal = Biochemistry and Cell Biology | volume = 70 | issue = 10–11 | pages = 1174–86 | year = 1992 | pmid = 1363623 | doi = 10.1139/o92-163 }}</ref>

The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of the eukaryotic cell. The majority of its resident proteins are retained within it through a retention [[Structural motif|motif]]. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences are [[KDEL (amino acid sequence)|KDEL]] for lumen-located proteins and [[KKXX (amino acid sequence)|KKXX]] for transmembrane proteins.<ref>{{cite journal | vauthors = Stornaiuolo M, Lotti LV, Borgese N, Torrisi MR, Mottola G, Martire G, Bonatti S | title = KDEL and KKXX retrieval signals appended to the same reporter protein determine different trafficking between endoplasmic reticulum, intermediate compartment, and Golgi complex | journal = Molecular Biology of the Cell | volume = 14 | issue = 3 | pages = 889–902 | date = March 2003 | pmid = 12631711 | pmc = 151567 | doi = 10.1091/mbc.E02-08-0468 }}</ref> However, variations of KDEL and KKXX do occur, and other sequences can also give rise to endoplasmic reticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDEL ([[KDELR1|1]], [[KDELR2|2]] and [[KDELR3|3]]) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.<ref>{{cite journal | vauthors = Raykhel I, Alanen H, Salo K, Jurvansuu J, Nguyen VD, Latva-Ranta M, Ruddock L | title = A molecular specificity code for the three mammalian KDEL receptors | journal = The Journal of Cell Biology | volume = 179 | issue = 6 | pages = 1193–204 | date = December 2007 | pmid = 18086916 | pmc = 2140024 | doi = 10.1083/jcb.200705180 }}</ref>

===Bioenergetics regulation of ER ATP supply by a CaATiER mechanism===
[[File:CaATiER model 081219.jpg|thumb|Ca2+-antagonized transport into the endoplasmic reticulum (CaATiER) model]]
The endoplasmic reticulum does not harbor an ATP-regeneration machinery, and therefore requires ATP import from mitochondria. The imported ATP is vital for the ER to carry out its house keeping cellular functions, such as for protein folding and trafficking.<ref>{{cite journal |last1=Clairmont |first1=CA |last2=De Maio |first2=A |last3=Hirschberg |first3=CB |title=Translocation of ATP into the lumen of rough endoplasmic reticulum-derived vesicles and its binding to luminal proteins including BiP (GRP 78) and GRP 94. |journal=The Journal of Biological Chemistry |date=25 February 1992 |volume=267 |issue=6 |pages=3983–90 |doi=10.1016/S0021-9258(19)50622-6 |pmid=1740446 |doi-access=free }}</ref>

The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized,<ref>{{cite journal |last1=Klein |first1=Marie-Christine |last2=Zimmermann |first2=Katharina |last3=Schorr |first3=Stefan |last4=Landini |first4=Martina |last5=Klemens |first5=Patrick A. W. |last6=Altensell |first6=Jacqueline |last7=Jung |first7=Martin |last8=Krause |first8=Elmar |last9=Nguyen |first9=Duy |last10=Helms |first10=Volkhard |last11=Rettig |first11=Jens |last12=Fecher-Trost |first12=Claudia |last13=Cavalié |first13=Adolfo |last14=Hoth |first14=Markus |last15=Bogeski |first15=Ivan |last16=Neuhaus |first16=H. Ekkehard |last17=Zimmermann |first17=Richard |last18=Lang |first18=Sven |last19=Haferkamp |first19=Ilka |title=AXER is an ATP/ADP exchanger in the membrane of the endoplasmic reticulum |journal=Nature Communications |date=28 August 2018 |volume=9 |issue=1 |pages=3489 |doi=10.1038/s41467-018-06003-9 |pmid=30154480 |pmc=6113206 |bibcode=2018NatCo...9.3489K }}</ref> and the mitochondria supply ATP to the ER through a ''Ca<sup>2+</sup>-antagonized transport into the ER'' (''CaATiER'') mechanism.<ref>{{cite journal |last1=Yong |first1=Jing |last2=Bischof |first2=Helmut |last3=Burgstaller |first3=Sandra |last4=Siirin |first4=Marina |last5=Murphy |first5=Anne |last6=Malli |first6=Roland |last7=Kaufman |first7=Randal J |title=Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca<sup>2+</sup> |journal=eLife |date=9 September 2019 |volume=8 |doi=10.7554/eLife.49682 |pmid=31498082 |pmc=6763289 |doi-access=free }}</ref> The ''CaATiER'' mechanism shows sensitivity to cytosolic Ca<sup>2+</sup> ranging from high nM to low μM range, with the Ca<sup>2+</sup>-sensing element yet to be identified and validated.<ref>{{Cite journal |last1=Yong |first1=Jing |last2=Bischof |first2=Helmut |last3=Burgstaller |first3=Sandra |last4=Siirin |first4=Marina |last5=Murphy |first5=Anne |last6=Malli |first6=Roland |last7=Kaufman |first7=Randal J |title=Mitochondria supply ATP to the ER through a mechanism antagonized by cytosolic Ca2+ |journal=eLife |date=2019 |volume=8 |pages=e49682 |doi=10.7554/eLife.49682 |doi-access=free |issn=2050-084X |pmc=6763289 |pmid=31498082}}</ref>

==Clinical significance==
Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia<ref>{{cite journal |last1=Yong |first1=Jing |last2=Johnson |first2=James D. |last3=Arvan |first3=Peter |last4=Han |first4=Jaeseok |last5=Kaufman |first5=Randal J. |title=Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus |journal=Nature Reviews Endocrinology |date=August 2021 |volume=17 |issue=8 |pages=455–467 |doi=10.1038/s41574-021-00510-4 |pmid=34163039 |pmc=8765009 }}</ref> and consequently peripheral insulin resistance associated with obesity in humans.<ref>{{cite journal |last1=van Vliet |first1=Stephan |last2=Koh |first2=Han-Chow E. |last3=Patterson |first3=Bruce W. |last4=Yoshino |first4=Mihoko |last5=LaForest |first5=Richard |last6=Gropler |first6=Robert J. |last7=Klein |first7=Samuel |last8=Mittendorfer |first8=Bettina |title=Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance |journal=Diabetes |date=1 October 2020 |volume=69 |issue=10 |pages=2112–2119 |doi=10.2337/db20-0377 |pmid=32651241 |pmc=7506835 }}</ref> Human clinical trials also suggested a causal link between obesity-induced increase in insulin secretion and peripheral insulin resistance.<ref>{{cite journal |last1=Mittendorfer |first1=Bettina |last2=Patterson |first2=Bruce W. |last3=Smith |first3=Gordon I. |last4=Yoshino |first4=Mihoko |last5=Klein |first5=Samuel |title=β Cell function and plasma insulin clearance in people with obesity and different glycemic status |journal=Journal of Clinical Investigation |date=1 February 2022 |volume=132 |issue=3 |pages=e154068 |doi=10.1172/JCI154068 |pmid=34905513 |pmc=8803344 }}</ref>

Abnormalities in [[XBP1]] lead to a heightened [[XBP1#Endoplasmic reticulum stress response|endoplasmic reticulum stress response]] and subsequently causes a higher susceptibility for inflammatory processes that may even contribute to [[Alzheimer's disease]].<ref name="Casas-Tinto-2011">{{cite journal | vauthors = Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P | title = The ER stress factor XBP1s prevents amyloid-beta neurotoxicity | journal = Human Molecular Genetics | volume = 20 | issue = 11 | pages = 2144–60 | date = June 2011 | pmid = 21389082 | pmc = 3090193 | doi = 10.1093/hmg/ddr100 }}</ref>  In the [[Colon (anatomy)|colon]], XBP1 anomalies have been linked to the inflammatory bowel diseases including [[Crohn's disease]].<ref name="Kaser-2008">{{cite journal | vauthors = Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS | title = XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease | journal = Cell | volume = 134 | issue = 5 | pages = 743–56 | date = September 2008 | pmid = 18775308 | pmc = 2586148 | doi = 10.1016/j.cell.2008.07.021 }}</ref>

The [[unfolded protein response]] (UPR) is a [[cellular stress response]] related to the endoplasmic reticulum.<ref>{{cite web |url=https://www.ibiology.org/cell-biology/unfolded-protein-response/ |title=Peter Walter's Short Talk: Unfolding the UPR |publisher=iBiology |first=Peter |last=Walter }}</ref> The UPR is activated in response to an accumulation of unfolded or misfolded [[protein]]s in the [[Lumen (anatomy)|lumen]] of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein [[translation (genetics)|translation]], degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular [[Chaperone (protein)|chaperones]] involved in [[protein folding]]. Sustained overactivation of the UPR has been implicated in [[prion]] diseases as well as several other [[neurodegeneration|neurodegenerative diseases]] and the inhibition of the UPR could become a treatment for those diseases.<ref>{{cite journal | vauthors = Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, Mallucci GR | title = Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice | journal = Science Translational Medicine | volume = 5 | issue = 206 | pages = 206ra138 | date = October 2013 | pmid = 24107777 | doi = 10.1126/scitranslmed.3006767 | s2cid = 25570626 }}</ref>

== See also ==
* [[Ribosome-associated vesicle]]

== References ==
{{reflist|32em}}

== External links ==
* [https://endoplasmicreticulum.us/ Endoplasmic Reticulum- Structure, Types & Functions]
* [https://www.stockmystory.com/endoplasmic-reticulum-rough-smooth-biology/ Endoplasmic Reticulum]
{{Commons category|Endoplasmic reticulum}}
* [http://opm.phar.umich.edu/atlas.php?membrane=Endoplasmic%20reticulum%20membrane Lipid and protein composition of Endoplasmic reticulum] in [[OPM database]]
* [http://multimedia.mcb.harvard.edu/media.html Animations of the various cell functions referenced here] {{Webarchive|url=https://web.archive.org/web/20080422024412/http://multimedia.mcb.harvard.edu/media.html |date=2008-04-22 }}

{{organelles}}

{{Authority control}}

[[Category:Endoplasmic reticulum]]
[[Category:Cell anatomy]]
[[Category:Cell biology]]
[[Category:Eukaryotic cell anatomy]]
[[Category:Organelles]]