Editing Endoplasmic reticulum (section)

==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>