Identification of Human Plasma Proteins as Major Clients for the Extracellular Chaperone Clusterin

Wyatt, Amy R.; Wilson, Mark R.

doi:10.1074/jbc.m109.079566

Cited by 39 publications

(45 citation statements)

References 77 publications

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Section: Biochemistry and Functions Of Sclusupporting

confidence: 57%

“…megalin)-mediated endocytosis and lysosomal degradation [51]. This hypothesis is supported by a recent study showing that sCLU in the blood binds to a panel of proteins, including ceruloplasmin, fibrinogen, and albumin, in response to physiologically relevant stress [52].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.…”

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confidence: 56%

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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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Section: Biochemistry and Functions Of Sclusupporting

confidence: 57%

supporting

confidence: 56%

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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“…Similarly, shear stress of 40 -60 dynes/cm 2 is physiologically relevant and simulates a degree of the variability present in human circulation: blood is constantly exposed to a variable arterial shear stress ϳ10 -70 dynes/cm 2 in health, although this ranges up to levels greater than 100 dynes/cm 2 in pathological states (71). Similar stresses achieved using similar techniques have been used to demonstrate physiologically relevant chaperone activity in clusterin (5,72).…”

Section: Discussionmentioning

confidence: 67%

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

Finn

Nunez

Sunde

et al. 2012

Journal of Biological Chemistry

134

101

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Background: Serum albumin is a highly abundant circulating protein and may have chaperone-like activity. Results: Serum albumin titratably inhibits aggregation and amyloid formation of client proteins and maintains chaperone-like activity under physiological conditions. Conclusion: The chaperone-like activity of serum albumin suggests it protects against protein misfolding and aggregation. Significance: This may have implications for protein misfolding disorders of the extracellular compartment.

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“…Inflammation is a state in which many stresses capable of inducing protein misfolding and aggregation are elevated; therefore, it is likely that proteostasis mechanisms will be enhanced during inflammatory events. Moreover, it has been shown that many acute-phase proteins are susceptible to stress-induced misfolding and major endogenous clients for holdase chaperones in human blood plasma (65)(66)(67). To survive periods of increased physiological stress, cells use several different strategies to prevent the accumulation of misfolded proteins (68)(69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

Wyatt

Kumita

Mifsud

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypochlorite, an oxidant generated in vivo by the innate immune system, kills invading pathogens largely by inducing the misfolding of microbial proteins. Concomitantly, the nonspecific activity of hypochlorite also damages host proteins, and the accumulation of damaged (misfolded) proteins is implicated in the pathology of a variety of debilitating human disorders (e.g., Alzheimer's disease, atherosclerosis, and arthritis). It is well-known that cells respond to oxidative stress by up-regulating proteostasis machinery, but the direct activation of mammalian chaperones by hypochlorite has not, to our knowledge, been previously reported. In this study, we show that hypochlorite-induced modifications of human α 2 -macroglobulin (α 2 M) markedly increase its chaperone activity by generating species, particularly dimers formed by dissociation of the native tetramer, which have enhanced surface hydrophobicity. Moreover, dimeric α 2 M is generated in whole-blood plasma in the presence of physiologically relevant amounts of hypochlorite. The chaperone activity of hypochlorite-modified α 2 M involves the formation of stable soluble complexes with misfolded client proteins, including heat-denatured enzymes, oxidized fibrinogen, oxidized LDL, and native or oxidized amyloid β-peptide (Aβ 1-42 ). Here, we show that hypochlorite-modified α 2 M delivers its misfolded cargo to lipoprotein receptors on macrophages and reduces Aβ 1-42 neurotoxicity. Our results support the conclusion that α 2 M is a specialized chaperone that prevents the extracellular accumulation of misfolded and potentially pathogenic proteins, particularly during innate immune system activity. molecular chaperone | inflammation | protein folding | clearance H ypochlorite, a potent oxidant produced by immune cells through the myeloperoxidase-H 2 O 2 -chloride system, kills invading microbes predominately by inducing the misfolding and aggregation of their proteins (1). The effects of hypochlorite, however, are nonspecific; therefore, when generated in vivo, the host organism suffers collateral damage (reviewed in refs. 2 and 3). During inflammation, hypochlorite production is accompanied by additional stresses, which are themselves capable of inducing protein misfolding (e.g., increased temperature and lowered pH); it is, therefore, not surprising that, in a large number of diseases [e.g., atherosclerosis (4), Alzheimer's disease (5, 6), age-related macular degeneration (7), and arthritis (8)], inflammatory pathology is associated with the accumulation of misfolded proteins.α 2 -Macroglobulin (α 2 M) is a highly abundant secreted protein that is best known for its ability to trap proteases (9); α 2 M can, however, interact with a broad range of molecules, and consequently, many other biological roles have been suggested, including targeting cytokines for clearance, sequestration of zinc, and opsonization of bacteria (reviewed in ref. 10). Furthermore, α 2 M has been identified as one of a small number of abundant extracellular chaperones (11). Although our un...

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Identification of Human Plasma Proteins as Major Clients for the Extracellular Chaperone Clusterin

Cited by 39 publications

References 77 publications

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

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

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin

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Identification of Human Plasma Proteins as Major Clients for the Extracellular Chaperone Clusterin

Cited by 39 publications

References 77 publications

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

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

Serum Albumin Prevents Protein Aggregation and Amyloid Formation and Retains Chaperone-like Activity in the Presence of Physiological Ligands

Hypochlorite-induced structural modifications enhance the chaperone activity of human α2-macroglobulin

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Hypochlorite-induced structural modifications enhance the chaperone activity of human α₂-macroglobulin