Life and death of a BiP substrate

Abstract

BiP is the mammalian endoplasmic reticulum (ER) Hsp70 orthologue that plays a major role in all functions of this organelle including the seemingly opposing functions of aiding the maturation of unfolded nascent proteins and identifying and targeting chronically unfolded proteins for degradation. The recent identification of mammalian BiP co-factors combined with delineation of the ER degradation machinery and data suggesting that the ER is subdivided into unique regions helps explain how these different functions can occur in the same organelle and raises some unresolved issues.

Protein Folding and Quality Control in the ER

“…In addition to the CNX/CRT complex, the other major chaperone system in the ER is the BiP/GRP78 or Hsp70 system (Hendershot 2004;Dudek et al 2009;Otero et al 2010). BiP (binding immunoglobulin protein) is one of the most abundant ER chaperones and serves multiple roles in the ER ranging from productive folding to ERAD.…”

“…The DnaJ family proteins, cochaperones of BiP, play a crucial role in regulating its various activities. Accumulated evidence suggests that ERdj3 and ERdj6 are primarily involved in productive-folding (ERAF), whereas ERdj4 and ERdj5 predominantly affect ERAD (Otero et al 2010). The process of transition from folding to degradation is far from clear.…”

“…Presumably, the retention time of a substrate by BiP and its cofactors (e.g., ERdj3/6) may determine its fate. Prolonged retention would recruit other cofactors involved in ERAD, such as ERdj4/5 and p97/VCP (Otero et al 2010). HERP, a membrane-bound ubiquitin (Ub)-like protein, has been implicated in the efficient delivery of nonglycosylated substrates to the proteasome (Okuda- Shimizu and Hendershot 2007).…”

Protein Folding in the Endoplasmic Reticulum

“…In addition to controlling the localization and activity of Hsp70s, J-domain proteins may also bind the substrate themselves and help with the initial delivery of the substrate to the Hsp70 chaperone. In the mammalian ER, there are seven J-domain proteins (ERdj1-7) that assist with the diverse functions of BiP in the ER (Otero et al 2010). ERdj1/Mtj1p and ERdj2/Sec63 are membrane-embedded and translocon-associated J-proteins.…”

C-terminal Mutations Destabilize SIL1/BAP and Can Cause Marinesco-Sjögren Syndrome

“…Our finding that overexpression of BiP suppressed the secretion of wild-type SIL1 argues that this is likely to be the normal mechanism of SIL1 retention. It is very possible that this mechanism extends to other soluble ER-resident proteins that do not have ER retention sequences, including many of the other ER-localized DnaJlike proteins (42). In keeping with this, studies to measure the concentration of BiP and resident ER-localized DnaJ-like proteins found that the concentration of BiP was significantly greater than the combined concentration of the ERdj proteins (43).…”