Expanding the cellular molecular chaperone network through the ubiquitous cochaperones

Echtenkamp, Frank; Freeman, Brian C.

doi:10.1016/j.bbamcr.2011.08.011

Cited by 29 publications

(29 citation statements)

References 34 publications

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“…HSP90 client proteins require its activity either for the folding step that occurs during their synthesis and/or maturation (68) or to support the active conformation of their enzymatic activity, as is the case for many kinases and ubiquitin E3 ligases (69). In the first case, once the clients have achieved their mature folding, their stability and/or function usually no longer rely on HSP90 (68). The type of HSP90 client the L polymerase is was evaluated by two complementary approaches.…”

Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

Bloyet

Welsch

Enchéry

et al. 2016

J Virol

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Nonsegmented negative-stranded RNA viruses, or members of the order Mononegavirales, share a conserved gene order and the use of elaborate transcription and replication machinery made up of at least four molecular partners. These partners have coevolved with the acquisition of the permanent encapsidation of the entire genome by the nucleoprotein (N) and the use of this N-RNA complex as a template for the viral polymerase composed of the phosphoprotein (P) and the large enzymatic protein (L). Not only is P required for polymerase function, but it also stabilizes the L protein through an unknown underlying molecular mechanism. By using NVP-AUY922 and/or 17-dimethylaminoethylamino-17-demethoxygeldanamycin as specific inhibitors of cellular heat shock protein 90 (HSP90), we found that efficient chaperoning of L by HSP90 requires P in the measles, Nipah, and vesicular stomatitis viruses. While the production of P remains unchanged in the presence of HSP90 inhibitors, the production of soluble and functional L requires both P and HSP90 activity. Measles virus P can bind the N terminus of L in the absence of HSP90 activity. Both HSP90 and P are required for the folding of L, as evidenced by a luciferase reporter insert fused within measles virus L. HSP90 acts as a true chaperon; its activity is transient and dispensable for the activity of measles and Nipah virus polymerases of virion origin. That the cellular chaperoning of a viral polymerase into a soluble functional enzyme requires the assistance of another viral protein constitutes a new paradigm that seems to be conserved within the Mononegavirales order. IMPORTANCEViruses are obligate intracellular parasites that require a cellular environment for their replication. Some viruses particularly depend on the cellular chaperoning apparatus. We report here that for measles virus, successful chaperoning of the viral L polymerase mediated by heat shock protein 90 (HSP90) requires the presence of the viral phosphoprotein (P). Indeed, while P protein binds to the N terminus of L independently of HSP90 activity, both HSP90 and P are required to produce stable, soluble, folded, and functional L proteins. Once formed, the mature P؉L complex no longer requires HSP90 to exert its polymerase functions. Such a new paradigm for the maturation of a viral polymerase appears to be conserved in several members of the Mononegavirales order, including the Nipah and vesicular stomatitis viruses. Viruses with a nonsegmented negative-stranded RNA genome, or members of the order Mononegavirales, share a common and highly conserved genomic organization and replication machinery that are unique in the living world. Indeed, the L protein, or polymerase, which is endowed with all of the enzymatic activities required for the synthesis of RNA and the capping and polyadenylation of viral transcripts, cannot use naked viral genomic RNA in a processive way (1). Instead, L associates with the phosphoprotein (P) to dynamically anchor the polymerase complex to the nucleocapsid and/or to enable...

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Section: Hsp90 Activity Is Required For Mev Growth At a Postentry Stepmentioning

confidence: 99%

HSP90 Chaperoning in Addition to Phosphoprotein Required for Folding but Not for Supporting Enzymatic Activities of Measles and Nipah Virus L Polymerases

Bloyet

Welsch

Enchéry

et al. 2016

J Virol

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“…substrates for ERdj3), even those clients still associated with the relatively immobile translocation channel (Blais et al, 2010;Borgese et al, 2006;Nikonov et al, 2002;Ostrovsky et al, 2009). A number of chaperone co-factors, termed co-chaperones, regulate chaperone activities (Echtenkamp and Freeman, 2012;Laufen et al, 1999;Otero et al, 2010). Many co-chaperones are expressed at substoichiometric levels relative to chaperones (Schwanhäusser et al, 2011;Weitzmann et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

ERdj3 Regulates BiP Occupancy in Living Cells

Guo

Snapp

2013

Journal of Cell Science

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SummaryCo-chaperones regulate chaperone activities and are likely to impact a protein-folding environment as much as the chaperone itself. As co-chaperones are expressed substoichiometrically, the ability of co-chaperones to encounter a chaperone is crucial for chaperone activity. ERdj3, an abundant soluble endoplasmic reticulum (ER) co-chaperone of the Hsp70 BiP, stimulates the ATPase activity of BiP to increase BiP's affinity for client (or substrate) proteins. We investigated ERdj3 availability, how ERdj3 levels impact BiP availability, and the significance of J proteins for regulating BiP binding of clients in living cells. FRAP analysis revealed that overexpressed ERdj3-sfGFP dramatically decreases BiP-GFP mobility in a client-dependent manner. By contrast, ERdj3-GFP mobility remains low regardless of client protein levels. Native gels and co-immunoprecipitations established that ERdj3 associates with a large complex including Sec61a. Translocon binding probably ensures rapid encounters between emerging nascent peptides and stimulates BiP activity in the crucial early stages of secretory protein folding. Importantly, mutant BiP exhibited significantly increased mobility when it could not interact with any ERdjs. Thus, ERdjs appear to play the dual roles of increasing BiP affinity for clients and regulating delivery of clients to BiP. Our data suggest that BiP engagement of clients is enhanced in ER subdomains enriched in ERdj proteins.

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“…Hsp70s function in conjunction with a set of Hsp40 cochaperones, collectively called J-proteins, because they all contain a J-domain that is required for interaction with Hsp70 (78). Hsp40s exhibit somewhat distinct client specificities; thus, Hsp70's client affinity is in part fine-tuned by its co-chaperone (79). In addition, Hsp70s function with nucleotide exchange factors, which facilitate ADP-ATP exchange.…”

Section: Hsp70mentioning

confidence: 99%