Editing Clusterin

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox gene}}

'''Clusterin''' is a [[protein]] that in humans is encoded by the ''CLU'' [[gene]] on chromosome 8.<ref name="entrez">{{cite web | title = Entrez Gene: clusterin | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1191 }}</ref> CLU is an extracellular [[molecular chaperone]] which binds to misfolded proteins in body fluids to neutralise their toxicity and mediate their cellular uptake by receptor-mediated endocytosis. Once internalised by cells, complexes between CLU and misfolded proteins are trafficked to lysosomes where they are degraded.<ref>{{Cite journal | vauthors = Wyatt AR, Yerbury JJ, Ecroyd H, Wilson MR | title = Extracellular chaperones and proteostasis | journal = Annual Review of Biochemistry | volume = 82 | pages = 295–322 | date = 2013 | pmid = 23350744 | doi = 10.1146/annurev-biochem-072711-163904 | url = https://pubmed.ncbi.nlm.nih.gov/23350744 | issn = 1545-4509 }}</ref> CLU is involved in many [[disease]]s including [[neurodegenerative disease]]s, [[cancer]]s, [[inflammation|inflammatory diseases]], and [[aging]].<ref name="Koltai_2014">{{cite journal | vauthors = Koltai T | title = Clusterin: a key player in cancer chemoresistance and its inhibition | journal = Oncotargets and Therapy | volume = 7 | pages = 447–456 | date = 2014 | pmid = 24672247 | pmc = 3964162 | doi = 10.2147/OTT.S58622 | doi-access = free }}</ref><ref name="Sansanwal_2015">{{cite journal | vauthors = Sansanwal P, Li L, Sarwal MM | title = Inhibition of intracellular clusterin attenuates cell death in nephropathic cystinosis | journal = Journal of the American Society of Nephrology | volume = 26 | issue = 3 | pages = 612–625 | date = Mar 2015 | pmid = 25071085 | pmc = 4341467 | doi = 10.1681/ASN.2013060577 }}</ref><ref name="Lin_2014">{{cite journal | vauthors = Lin CC, Tsai P, Sun HY, Hsu MC, Lee JC, Wu IC, Tsao CW, Chang TT, Young KC | title = Apolipoprotein J, a glucose-upregulated molecular chaperone, stabilizes core and NS5A to promote infectious hepatitis C virus virion production | journal = Journal of Hepatology | volume = 61 | issue = 5 | pages = 984–993 | date = Nov 2014 | pmid = 24996046 | doi = 10.1016/j.jhep.2014.06.026 }}</ref>

==Structure==

The ''CLU'' gene contains nine [[exon]]s and a variety of mRNA isoforms can be detected, although most of these are only ever expressed at very low levels (< 0.3% of the total). The full-length mRNA encoding the secreted isoform is by far the dominant species transcribed.<ref>{{Cite journal | vauthors = Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdörfer M | title = Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-κB signaling pathway | journal = PLOS ONE | volume = 8 | issue = 9 | pages = e75303 | date = 2013 | pmid = 24073260 | pmc = 3779157 | doi = 10.1371/journal.pone.0075303 | doi-access = free | issn = 1932-6203 | bibcode = 2013PLoSO...875303P }}</ref> Secreted CLU (apolipoprotein J) is an approximately 60 kDa disulfide-linked heterodimeric glycoprotein which migrates in SDS-PAGE with an apparent molecular mass of 75-80 kDa.<ref>{{Cite journal | vauthors = Kapron JT, Hilliard GM, Lakins JN, Tenniswood MP, West KA, Carr SA, Crabb JW | title = Identification and characterization of glycosylation sites in human serum clusterin | journal = Protein Science : A Publication of the Protein Society | volume = 6 | issue = 10 | pages = 2120–2133 | date = 1997 | pmid = 9336835 | pmc = 2143570 | doi = 10.1002/pro.5560061007 | issn = 0961-8368 }}</ref> Mature CLU is composed of disulfide-linked α- and β-chains. Although multiple previous publications proposed the existence of N-terminally truncated CLU protein isoforms in different cell compartments, recent work has highlighted the lack of direct evidence for this <ref name="Satapathy_2021">{{Cite journal | vauthors = Satapathy S, Wilson MR | title = The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis | journal = Trends in Biochemical Sciences | volume = 46 | issue = 8 | pages = 652–660 | date = 2021 | pmid = 33573881 | doi = 10.1016/j.tibs.2021.01.005 | url = https://pubmed.ncbi.nlm.nih.gov/33573881 | issn = 0968-0004 | s2cid = 231897964 }}</ref> and shown that the full-length CLU polypeptide, with variable levels of glycosylation (and hence variable apparent mass), can translocate from the ER/Golgi to the cytosol and nucleus during stress.<ref>{{Cite journal | vauthors = Satapathy S, Walker H, Brown J, Gambin Y, Wilson MR | title = The N-end rule pathway regulates ER stress-induced clusterin release to the cytosol where it directs misfolded proteins for degradation | journal = Cell Reports | volume = 42 | issue = 9 | pages = 113059 | date = 2023-09-26 | pmid = 37660295 | doi = 10.1016/j.celrep.2023.113059 | issn = 2211-1247 | doi-access = free }}</ref>

== Function ==

Clusterin was first identified in ram rete testis fluid where it was shown to elicit in vitro clustering of rat Sertoli cells and erythrocytes, hence its name.<ref name="Fritz_1983">{{cite journal | vauthors = Fritz IB, Burdzy K, Sétchell B, Blaschuk O | title = Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro | journal = Biology of Reproduction | volume = 28 | issue = 5 | pages = 1173–1188 | date = Jun 1983 | pmid = 6871313 | doi = 10.1095/biolreprod28.5.1173 | doi-access = free }}</ref>

CLU has functional similarities to members of the small [[heat shock protein]] family and is thus a [[chaperone (protein)|molecular chaperone]]. Unlike most other chaperone proteins, which aid [[intracellular]] proteins, CLU is trafficked through the ER/Golgi before normally being secreted. Within the secretory system, CLU has been suggested to facilitate the folding of secreted proteins in an [[Adenosine triphosphate|ATP]]-independent way.<ref name="Lin_2014" /> The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it been implicated in a number of biological processes, including [[lipid]] transport, membrane recycling, [[cell adhesion]], [[programmed cell death]], and [[complement system|complement]]-mediated [[cell lysis]].<ref name="Koltai_2014" /><ref name="Sansanwal_2015" /><ref name="Lin_2014" /> Overexpression of secretory CLU can protect cells from apoptosis induced by cellular stress, such as [[chemotherapy]], [[radiotherapy]], or [[androgen]]/[[estrogen]] depletion. CLU has been suggested to promote cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the [[phosphatidylinositol 3-kinase]]/[[protein kinase B]] pathway, modulation of [[extracellular signal-regulated kinases|extracellular signal-regulated kinase]] (ERK) 1/2 [[signal transduction|signaling]] and [[matrix metallopeptidase-9]] expression, promotion of [[angiogenesis]], and mediation of the nuclear factor kappa B ([[NF-κB]]) pathway. Meanwhile, its downregulation allows for [[p53]] activation, which then skews the proapoptotic:antiapoptotic ratio of present [[Bcl-2 family]] members, resulting in [[mitochondria]]l dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.<ref name="Koltai_2014" />

== Clinical significance ==

=== Alzheimer's disease ===
Two independent [[genome-wide association study|genome-wide association studies]] identified a statistical association between a [[single-nucleotide polymorphism]] (SNP) in the ''CLU'' gene and the risk of developing [[Alzheimer's disease]].<ref name="Harold_2009">{{cite journal | vauthors = Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J | author38-link = Martin Rossor | title = Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease | journal = Nature Genetics | volume = 41 | issue = 10 | pages = 1088–1093 | date = Oct 2009 | pmid = 19734902 | pmc = 2845877 | doi = 10.1038/ng.440 }}</ref><ref name="Lambert_2009">{{cite journal | vauthors = Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P | title = Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease | journal = Nature Genetics | volume = 41 | issue = 10 | pages = 1094–1099 | date = Oct 2009 | pmid = 19734903 | doi = 10.1038/ng.439 | s2cid = 24530130 }}</ref>

Subsequent studies found elevated clusterin (CLU) protein levels in the blood of individuals with Alzheimer's disease, and these levels were correlated with faster cognitive decline. However, increased CLU levels did not reliably predict the onset of the disease.<ref name="Schrijvers_2011">{{cite journal | vauthors = Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM | title = Plasma clusterin and the risk of Alzheimer disease | journal = JAMA | volume = 305 | issue = 13 | pages = 1322–1326 | date = Apr 2011 | pmid = 21467285 | doi = 10.1001/jama.2011.381 | s2cid = 36026598 }}</ref><ref>{{cite web | title = Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease | year = 2010 | url = https://www.sciencedaily.com/releases/2010/07/100705190536.htm# }}</ref>

CLU may also play a role in other neurodegenerative diseases, such as [[Huntington disease]].<ref name="Sansanwal_2015" />

=== Cancer ===
CLU has been implicated in multiple cancers through its role in promoting tumor cell survival and resistance to apoptosis. It facilitates the binding of BAX to Ku70, thereby preventing BAX from localizing to the [[outer mitochondrial membrane]] to initiate apoptosis.

In [[clear cell renal cell carcinoma]], CLU regulates ERK1/2 signaling and matrix [[metallopeptidase]]-9 expression to promote tumor [[cell migration]], invasion, and [[metastasis]]. In [[epithelial ovarian cancer]], CLU enhances [[angiogenesis]] and [[chemotherapy#Resistance|chemoresistance]]. It is also involved in the [[PI3K/AKT/mTOR pathway]] and [[NF-κB pathway]], further supporting cell survival and resistance to therapy.  In contrast, CLU expression is downregulated in [[testicular]] [[seminoma]], making these tumors more sensitive to chemotherapy. CLU has also been implicated in [[breast cancer]], [[pancreatic cancer]], [[hepatocellular carcinoma]], and [[melanoma]].

Due to its central role in tumor biology, CLU has been investigated as a therapeutic target. Inhibition of CLU enhances the efficacy of chemotherapeutic agents.<ref name="Koltai_2014" /> One promising agent, [[custirsen]], is an antisense oligonucleotide that targets CLU mRNA. It was shown to improve the activity of [[heat-shock protein 90|HSP90]] inhibitors by suppressing the heat shock response in castration-resistant [[prostate cancer]], and was evaluated in [[phase III clinical trial|phase III trials]].<ref name="Koltai_2014" /><ref name="Lin_2014" />

=== Infectious diseases ===
CLU is also involved in the host response to infection. In [[hepatitis C]] virus infection, CLU is upregulated in response to cellular stress and assists in viral assembly by stabilizing the viral core and NS5A proteins.<ref name="Lin_2014" />

=== Other conditions ===
Beyond its roles in neurodegeneration, cancer, and infection, CLU has been associated with conditions related to [[oxidative stress]], including [[aging]], [[glomerulonephritis]], [[atherosclerosis]], and [[myocardial infarction]].<ref name="Lin_2014" />

== Interactions ==

CLU has been shown to interact with many different protein ligands and several cell receptors.<ref name="Satapathy_2021" />

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Krumbiegel M, Pasutto F, Mardin CY, Weisschuh N, Paoli D, Gramer E, Zenkel M, Weber BH, Kruse FE, Schlötzer-Schrehardt U, Reis A | title = Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma | journal = Investigative Ophthalmology & Visual Science | volume = 50 | issue = 6 | pages = 2796–2801 | date = Jun 2009 | pmid = 19182256 | doi = 10.1167/iovs.08-2339 | doi-access = free }}
* {{cite journal | vauthors = Cerhan JR, Novak AJ, Fredericksen ZS, Wang AH, Liebow M, Call TG, Dogan A, Witzig TE, Ansell SM, Habermann TM, Kay NE, Slager SL | title = Risk of non-Hodgkin lymphoma in association with germline variation in complement genes | journal = British Journal of Haematology | volume = 145 | issue = 5 | pages = 614–623 | date = Jun 2009 | pmid = 19344414 | pmc = 2820509 | doi = 10.1111/j.1365-2141.2009.07675.x }}
* {{cite journal | vauthors = Trougakos IP, Gonos ES | title = Clusterin/apolipoprotein J in human aging and cancer | journal = The International Journal of Biochemistry & Cell Biology | volume = 34 | issue = 11 | pages = 1430–1448 | date = Nov 2002 | pmid = 12200037 | doi = 10.1016/S1357-2725(02)00041-9 }}
* {{cite journal | vauthors = Jenne DE, Tschopp J | title = Clusterin: the intriguing guises of a widely expressed glycoprotein | journal = Trends in Biochemical Sciences | volume = 17 | issue = 4 | pages = 154–159 | date = Apr 1992 | pmid = 1585460 | doi = 10.1016/0968-0004(92)90325-4 }}
* {{cite journal | vauthors = Ståhl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, Karpman D | title = A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome | journal = Molecular Immunology | volume = 46 | issue = 11–12 | pages = 2236–2243 | date = Jul 2009 | pmid = 19446882 | doi = 10.1016/j.molimm.2009.04.012 }}
* {{cite journal | vauthors = Balantinou E, Trougakos IP, Chondrogianni N, Margaritis LH, Gonos ES | title = Transcriptional and posttranslational regulation of clusterin by the two main cellular proteolytic pathways | journal = Free Radical Biology & Medicine | volume = 46 | issue = 9 | pages = 1267–1274 | date = May 2009 | pmid = 19353783 | doi = 10.1016/j.freeradbiomed.2009.01.025 }}
* {{cite journal | vauthors = Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X | title = Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer | journal = International Journal of Cancer | volume = 125 | issue = 4 | pages = 791–806 | date = Aug 2009 | pmid = 19391138 | doi = 10.1002/ijc.24316 | s2cid = 23162609 | doi-access = free }}
* {{cite journal | vauthors = Chou TY, Chen WC, Lee AC, Hung SM, Shih NY, Chen MY | title = Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway | journal = Cellular Signalling | volume = 21 | issue = 5 | pages = 704–711 | date = May 2009 | pmid = 19166932 | doi = 10.1016/j.cellsig.2009.01.008 }}
* {{cite journal | vauthors = Olsen SH, Ma L, Schnitzer B, Fullen DR | title = Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants | journal = Journal of Cutaneous Pathology | volume = 36 | issue = 3 | pages = 302–307 | date = Mar 2009 | pmid = 19220628 | doi = 10.1111/j.1600-0560.2008.01036.x | hdl = 2027.42/73222 | s2cid = 8915250 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/73222/1/j.1600-0560.2008.01036.x.pdf | hdl-access = free }}
* {{cite journal | vauthors = Aigelsreiter A, Janig E, Sostaric J, Pichler M, Unterthor D, Halasz J, Lackner C, Zatloukal K, Denk H | title = Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis | journal = Histopathology | volume = 54 | issue = 5 | pages = 561–570 | date = Apr 2009 | pmid = 19413638 | doi = 10.1111/j.1365-2559.2009.03258.x | s2cid = 21277859 }}
* {{cite journal | vauthors = Pucci S, Mazzarelli P, Paola M, Sesti F, Fabiola S, Boothman DA, David BA, Spagnoli LG, Luigi SG | title = Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression | journal = Cell Cycle | location = Georgetown, Tex. | volume = 8 | issue = 3 | pages = 473–481 | date = Feb 2009 | pmid = 19177010 | pmc = 2853871 | doi = 10.4161/cc.8.3.7652 }}
* {{cite journal | vauthors = Trougakos IP, Lourda M, Antonelou MH, Kletsas D, Gorgoulis VG, Papassideri IS, Zou Y, Margaritis LH, Boothman DA, Gonos ES | title = Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex | journal = Clinical Cancer Research| volume = 15 | issue = 1 | pages = 48–59 | date = Jan 2009 | pmid = 19118032 | pmc = 4483278 | doi = 10.1158/1078-0432.CCR-08-1805 }}
* {{cite journal | vauthors = Boland JM, Folpe AL, Hornick JL, Grogg KL | title = Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications | journal = The American Journal of Surgical Pathology | volume = 33 | issue = 8 | pages = 1225–1229 | date = Aug 2009 | pmid = 19542874 | doi = 10.1097/PAS.0b013e3181a6d86f | s2cid = 24444024 }}
* {{cite journal | vauthors = Chandra P, Plaza JA, Zuo Z, Diwan AH, Koeppen H, Duvic M, Medeiros LJ, Prieto VG | title = Clusterin expression correlates with stage and presence of large cells in mycosis fungoides | journal = American Journal of Clinical Pathology | volume = 131 | issue = 4 | pages = 511–515 | date = Apr 2009 | pmid = 19289586 | doi = 10.1309/AJCPH43ZDVLSOSNB | doi-access = free }}
* {{cite journal | vauthors = Rizzi F, Caccamo AE, Belloni L, Bettuzzi S | title = Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells | journal = Journal of Cellular Physiology | volume = 219 | issue = 2 | pages = 314–323 | date = May 2009 | pmid = 19137541 | doi = 10.1002/jcp.21671 | s2cid = 206047289 }}
* {{cite journal | vauthors = Liao FT, Lee YJ, Ko JL, Tsai CC, Tseng CJ, Sheu GT | title = Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells | journal = The Journal of General Virology | volume = 90 | issue = Pt 5 | pages = 1124–1134 | date = May 2009 | pmid = 19264665 | doi = 10.1099/vir.0.007211-0 | doi-access = free }}
* {{cite journal | vauthors = Shannan B, Seifert M, Boothman DA, Tilgen W, Reichrath J | title = Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control | journal = Journal of Molecular Histology | volume = 37 | issue = 5–7 | pages = 183–188 | date = Sep 2006 | pmid = 17048076 | doi = 10.1007/s10735-006-9052-7 | s2cid = 20041580 }}
* {{cite journal | vauthors = Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, Reichrath J | title = Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer | journal = Cell Death and Differentiation | volume = 13 | issue = 1 | pages = 12–19 | date = Jan 2006 | pmid = 16179938 | doi = 10.1038/sj.cdd.4401779 | doi-access = free }}
* {{cite journal | vauthors = Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y | title = Genome-wide association study of panic disorder in the Japanese population | journal = Journal of Human Genetics | volume = 54 | issue = 2 | pages = 122–126 | date = Feb 2009 | pmid = 19165232 | doi = 10.1038/jhg.2008.17 | doi-access = free }}
*{{cite journal | vauthors = Tunçdemir M, Ozturk M | title = The effects of ACE inhibitor and angiotensin receptor blocker on clusterin and apoptosis in the kidney tissue of streptozotocin-diabetic rats | journal = Journal of Molecular Histology | volume = 39 | issue = 6 | pages = 605–616 | date = Dec 2008 | pmid = 18949565 | doi = 10.1007/s10735-008-9201-2 | s2cid = 11598911 }}
{{refend}}

== External links ==
* {{MeshName|Clusterin}}
* [https://www.mabtech.com/knowledge-center/applied-research/apolipoproteins Apolipoproteins and Applied Research]

{{Glycoproteins}}
{{Chaperones}}

[[Category:Proteins]]