Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol

Nizard, Philippe; Tetley, Susanne; Dréan, Yves Le; Watrin, Tanguy; Goff, Pascale Le; Wilson, Mark R.; Michel, Denis

doi:10.1111/j.1600-0854.2007.00549.x

Cited by 129 publications

(136 citation statements)

References 43 publications

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“…It can also transit from the cell secretory system to the cytosol during certain stress conditions, although the reasons why this occurs remain to be established (Nizard et al, 2007). Clusterin mRNA is nearly ubiquitous in animal tissues, being found in locales as diverse as the rat prostate gland and quail neuroretinal cells.…”

Section: Clusterinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Section: Clusterinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

Self Cite

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“…One could speculate that accumulation in one of these cellular compartments leads to different biological outcomes. Indeed, nuclear CLU promotes apoptosis, whereas localization in the mitochondria or in the extracellular spaces promotes cell survival (Jones and Jomary, 2002;Zhang et al, 2005;Shannan et al, 2006;Nizard et al, 2007). To define the role of CLU in prostate tumourigenesis in vivo, we crossed CLU knockout (CluKo) with TRAMP mice.…”

Section: Introductionmentioning

confidence: 99%

Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

et al. 2009

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ApoJ/Clusterin (CLU) is a heterodimeric protein localized in the nucleus, cytoplasm or secretory organelles and involved in cell survival and neoplastic transformation. Its function in human cancer is still highly controversial. In this study, we examined the prostate of mice in which CLU has been genetically inactivated. Surprisingly, we observed transformation of the prostate epithelium in the majority of CLU knockout mice. Either PIN (prostate intraepithelial neoplasia) or differentiated carcinoma was observed in 100 and 87% of mice with homozygous or heterozygous deletion of CLU, respectively. Crossing CLU knockout with TRAMP (prostate cancer prone) mice results in a strong enhancement of metastatic spread. Finally, CLU depletion causes tumourigenesis in female TRAMP mice, which are normally cancer free. Mechanistically, deletion of CLU induces activation of nuclear factor-kB, a potentially oncogenic transcription factor important for the proliferation and survival of prostate cells.

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“…Inside human cells, in addition to nCLU isoform that is mainly localizing in the nucleus and triggers cell death [53], sCLU could redirect to the cytosol under cellular stress [8,54]. In mice, CLU in normal tissues (heart and kidney) is present as a single protein band at approximately 40 kDa in Western blot analysis in our studies [24,55,56], while in cultured cells from these tissues two protein bands at approximately 60 kDa and 40 kDa are detected [24,55,56], suggesting that mouse CLU probably is also retrotranslocated to the cytosol following exposure to sub lethal stress in culture conditions.…”

Section: Biochemistry and Functions Of Sclumentioning

confidence: 99%

“…The nCLU is translocated into the nucleus after translation andprobably without glycosylation [3], whereas the pre-secreted sCLU is targeted to ER and Golgi bodies glycosylation and cleavage between Arg-205 and Ser-206 to produce mature sCLU, a secreted disulfide-linked heterodimer of α-and β-chains [5][6][7]. Under certain stress conditions, sCLU however can be retrotranslocalized into the cytosol instead of secretion [8]. However, the cellular localization of all these isoforms and their expression are largely unknown.…”

Section: Clu Gene Isoforms and Cellular Localizationmentioning

confidence: 99%

From Humans to Experimental Models: The Cytoprotective Role of Clusterin in the Kidney

Guan¹,

Alnasser²,

Nguan

et al. 2014

Med Surg Urol

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Clusterin (CLU) is a chaperone-like protein and has been discovered more than thirty years ago; however, its biological significance is still not fully understood. This review aims to summarize the principal observations of CLU roles related to the kidney. In humans, three or more mRNA isoforms of CLU could be expressed due to different translation start sites, but only two forms of CLU protein, secreted (sCLU, isoform 2) and nuclear (nCLU, isoform 1), have been well characterized, whereas there is only sCLU form in mice. In the biopsies of renal tissue from patients, up regulated CLU expression has been found in rejecting kidney transplants or diseased kidneys, and a lower level of serum CLU is correlated with many types of kidney disease in patients. In mice, a deficiency in CLU expression specifically leads to the phenotype of age-dependent chronic glomerular injury -moderate to severe accumulation of the mesangial matrix, becomes more susceptible to ischemia-reperfusion injury (IRI), negatively impacts renal repair after IRI and worsens renal fibrosis after ureteral obstruction. All these observations may imply the biological significance of CLU for the maintenance of the tissue homeostasis in adult kidneys. However, how CLU protects the kidney from injury or by which extracellular and intracellular pathways mediate the cyto-protection of CLU in the kidney has not been well investigated. Understanding of the cyto-protective activities of CLU in the kidney could lead to the development of novel therapeutic strategies for the prevention and/or treatment of kidney injury or diseases. CLU Gene, Isoforms and Cellular LocalizationClusterin (CLU) protein was first discovered more than thirty years ago [1], and a large volume of research has been dedicated to it since -there are more than two thousand publications in Pubmed/NCBI databases when using 'clusterin' as a keyword search criteria today. Human CLU gene (NCBI Gene ID: 1191) is located at chromosome 8p21-p12, and consists of 10 exons, in which the first two exons are alternative (designated 1 and 1') [2]. Thus, CLU gene can be transcribed into at least three mRNA variants (NCBI Reference No.: NM_001831.3; NR_038335.1; NR_045494.1) or perhaps even more [3]. The mRNA isoform 1 is a major form of CLU mRNA, whereas other forms including mRNA isoform 2 collectively count for less than 1% of total CLU mRNA [3]. Two isoforms of CLU proteins have been well characterized; nuclear isoform of CLU (nCLU, isoform 1) containing the nuclear localization signal that is translated due to the splicing at exon 1 and 3 together placing a downstream AUG at exon 3 as the first available translation and lacking of exon 2 [3,4], while pre-secreted isoform of CLU (sCLU) containing the endoplasmic reticulum (ER)-targeting signalencoding in exon 2 [3]. The nCLU is translocated into the nucleus after translation andprobably without glycosylation [3], whereas the pre-secreted sCLU is targeted to ER and Golgi bodies glycosylation and cleavage between Arg-205 and Ser-206 to produc...

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Stress‐Induced Retrotranslocation of Clusterin/ApoJ into the Cytosol

Cited by 129 publications

References 43 publications

Extracellular Chaperones and Amyloids

Extracellular Chaperones and Amyloids

Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread

From Humans to Experimental Models: The Cytoprotective Role of Clusterin in the Kidney

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