Editing Proteasome (section)

==Response to cellular stress==
In response to cellular stresses&nbsp;– such as [[infection]], [[heat shock]], or [[reactive oxygen species|oxidative damage]]&nbsp;– [[heat shock protein]]s that identify misfolded or unfolded proteins and target them for proteasomal degradation are expressed. Both [[Hsp27]] and [[Hsp90]]—[[Chaperone (protein)|chaperone]] proteins have been implicated in increasing the activity of the ubiquitin-proteasome system, though they are not direct participants in the process.<ref name="Garrido">{{cite journal | vauthors = Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G | title = Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties | journal = Cell Cycle | volume = 5 | issue = 22 | pages = 2592–601 | date = November 2006 | pmid = 17106261 | doi = 10.4161/cc.5.22.3448 | doi-access = free }}</ref> [[Hsp70]], on the other hand, binds exposed [[hydrophobic]] patches on the surface of misfolded proteins and recruits E3 ubiquitin ligases such as CHIP to tag the proteins for proteasomal degradation.<ref name="Park">{{cite journal | vauthors = Park SH, Bolender N, Eisele F, Kostova Z, Takeuchi J, Coffino P, Wolf DH | title = The cytoplasmic Hsp70 chaperone machinery subjects misfolded and endoplasmic reticulum import-incompetent proteins to degradation via the ubiquitin-proteasome system | journal = Molecular Biology of the Cell | volume = 18 | issue = 1 | pages = 153–65 | date = January 2007 | pmid = 17065559 | pmc = 1751312 | doi = 10.1091/mbc.E06-04-0338 }}</ref> The CHIP protein (carboxyl terminus of Hsp70-interacting protein) is itself regulated via inhibition of interactions between the E3 enzyme CHIP and its E2 binding partner.<ref name="Dai">{{cite journal | vauthors = Dai Q, Qian SB, Li HH, McDonough H, Borchers C, Huang D, Takayama S, Younger JM, Ren HY, Cyr DM, Patterson C | title = Regulation of the cytoplasmic quality control protein degradation pathway by BAG2 | journal = The Journal of Biological Chemistry | volume = 280 | issue = 46 | pages = 38673–81 | date = November 2005 | pmid = 16169850 | doi = 10.1074/jbc.M507986200 | doi-access = free }}</ref>

Similar mechanisms exist to promote the degradation of [[redox|oxidatively damaged]] proteins via the proteasome system. In particular, proteasomes localized to the nucleus are regulated by [[Poly ADP ribose polymerase|PARP]] and actively degrade inappropriately oxidized [[histone]]s.<ref name="Bader">{{cite journal | vauthors = Bader N, Grune T | title = Protein oxidation and proteolysis | journal = Biological Chemistry | volume = 387 | issue = 10–11 | pages = 1351–5 | year = 2006 | pmid = 17081106 | doi = 10.1515/BC.2006.169 | s2cid = 30385354 }}</ref> Oxidized proteins, which often form large amorphous aggregates in the cell, can be degraded directly by the 20S core particle without the 19S regulatory cap and do not require ATP hydrolysis or tagging with ubiquitin.<ref name="Shringarpure" /> However, high levels of oxidative damage increases the degree of cross-linking between protein fragments, rendering the aggregates resistant to proteolysis. Larger numbers and sizes of such highly oxidized aggregates are associated with [[aging]].<ref name="Davies">{{cite journal | vauthors = Davies KJ | title = Degradation of oxidized proteins by the 20S proteasome | journal = Biochimie | volume = 83 | issue = 3–4 | pages = 301–10 | year = 2003 | pmid = 11295490 | doi = 10.1016/S0300-9084(01)01250-0 }}</ref>

Dysregulation of the ubiquitin proteasome system may contribute to several neural diseases. It may lead to brain tumors such as [[astrocytomas]].<ref name=Lehman>{{cite journal | vauthors = Lehman NL | title = The ubiquitin proteasome system in neuropathology | journal = Acta Neuropathologica | volume = 118 | issue = 3 | pages = 329–47 | date = September 2009 | pmid = 19597829 | pmc = 2716447 | doi = 10.1007/s00401-009-0560-x }}</ref> In some of the late-onset [[neurodegenerative]] diseases that share aggregation of misfolded proteins as a common feature, such as [[Parkinson's disease]] and [[Alzheimer's disease]], large insoluble aggregates of misfolded proteins can form and then result in [[neurotoxicity]], through mechanisms that are not yet well understood. Decreased proteasome activity has been suggested as a cause of aggregation and [[Lewy body]] formation in Parkinson's.<ref name="McNaught">{{cite journal | vauthors = McNaught KS, Jackson T, JnoBaptiste R, Kapustin A, Olanow CW | title = Proteasomal dysfunction in sporadic Parkinson's disease | journal = Neurology | volume = 66 | issue = 10 Suppl 4 | pages = S37–49 | date = May 2006 | pmid = 16717251 | doi = 10.1212/01.wnl.0000221745.58886.2e | doi-access = free }}</ref> This hypothesis is supported by the observation that [[yeast]] models of Parkinson's are more susceptible to toxicity from [[alpha-synuclein|α-synuclein]], the major protein component of Lewy bodies, under conditions of low proteasome activity.<ref name="Sharma">{{cite journal | vauthors = Sharma N, Brandis KA, Herrera SK, Johnson BE, Vaidya T, Shrestha R, Debburman SK | title = alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress | journal = Journal of Molecular Neuroscience | volume = 28 | issue = 2 | pages = 161–78 | year = 2006 | pmid = 16679556 | doi = 10.1385/JMN:28:2:161 | s2cid = 27762513 }}</ref> Impaired proteasomal activity may underlie cognitive disorders such as the [[autism spectrum disorder]]s, and muscle and nerve diseases such as [[inclusion body myopathy]].<ref name=Lehman/>