JAMP optimizes ERAD to protect cells from unfolded proteins

Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Molecular biology of the cell (Impact Factor: 4.47). 10/2008; 19(11):5019-28. DOI: 10.1091/mbc.E08-08-0839
Source: PubMed


Clearance of misfolded proteins from the ER is central for maintenance of cellular homeostasis. This process requires coordinated recognition, ER-cytosol translocation, and finally ubiquitination-dependent proteasomal degradation. Here, we identify an ER resident seven-transmembrane protein (JAMP) that links ER chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits, thereby optimizing degradation of misfolded proteins. Elevated JAMP expression promotes localization of proteasomes at the ER, with a concomitant effect on degradation of specific ER-resident misfolded proteins, whereas inhibiting JAMP promotes the opposite response. Correspondingly, a jamp-1 deleted Caenorhabditis elegans strain exhibits hypersensitivity to ER stress and increased UPR. Using biochemical and genetic approaches, we identify JAMP as important component for coordinated clearance of misfolded proteins from the ER.

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Available from: Hediye Erdjument-Bromage, Apr 29, 2014
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    • "Many components of the ERAD pathway are also conserved between C. elegans and mammals [18-23]. Mutations in proteins involved in ERAD can be easily detected in C. elegans as they increase ER stress levels and increase sensitivity to agents that induce ER stress [19,20,22-24]. "
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    ABSTRACT: Erlins are highly conserved proteins associated with lipid rafts within the endoplasmic reticulum (ER). Biochemical studies in mammalian cell lines have shown that erlins are required for ER associated protein degradation (ERAD) of activated inositol-1,4,5-trisphosphate receptors (IP3Rs), implying that erlin proteins might negatively regulate IP3R signalling. In humans, loss of erlin function appears to cause progressive intellectual disability, motor dysfunction and joint contractures. However, it is unknown if defects in IP3R ERAD are the underlying cause of this disease phenotype, whether ERAD of activated IP3Rs is the only function of erlin proteins, and what role ERAD plays in regulating IP3R-dependent processes in the context of an intact animal or embryo. In this study, we characterize the erlin homologue of the nematode Caenorhabditis elegans and examine erlin function in vivo. We specifically set out to test whether C. elegans erlin modulates IP3R-dependent processes, such as egg laying, embryonic development and defecation rates. We also explore the possibility that erlin might play a more general role in the ERAD pathway of C. elegans. We first show that the C. elegans erlin homologue, ERL-1, is highly similar to mammalian erlins with respect to amino acid sequence, domain structure, biochemical properties and subcellular location. ERL-1 is present throughout the C. elegans embryo; in adult worms, ERL-1 appears restricted to the germline. The expression pattern of ERL-1 thus only partially overlaps with that of ITR-1, eliminating the possibility of ERL-1 being a ubiquitous and necessary regulator of ITR-1. We show that loss of ERL-1 does not affect overall phenotype, or alter brood size, embryonic development or defecation cycle length in either wild type or sensitized itr-1 mutant animals. Moreover we show that ERL-1 deficient worms respond normally to ER stress conditions, suggesting that ERL-1 is not an essential component of the general ERAD pathway. Although loss of erlin function apparently causes a strong phenotype in humans, no such effect is seen in C. elegans. C. elegans erlin does not appear to be a ubiquitous major modulator of IP3 receptor activity nor does erlin appear to play a major role in ERAD.
    Full-text · Article · Jan 2012 · BMC Cell Biology
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    • "Fig. 5 shows the different effects of the taurine and the taurine-free treatment with different doses. This result strongly implies that taurine helped the worms recover from the negative effect of ER stress on their muscular activity [25-28]. "
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    ABSTRACT: ER stress is a strong indicator of whether or not a cell is undergoing physiological stress. C. elegans is a practical system of characterizing the effect of ER stress at the in vivo or organismal level. This study characterized taurine's anti-ER stress potential employing western blotting on ER stress markers and assays of motility, lifespan comparison, and fecundity measurement. When treated with tunicamycin, C. elegans showed the typical ER stress symptoms. It showed a higher expression of hsp-70 and skn-1 than the non-treated control. Survivorship significantly decreased under tunicamycin treatment, and the offspring number also decreased. During the synchronized culture under ER stress conditions, the C. elegans showed early signs of aging especially between L3 and L4 within their life span, along with lowered motility. The worms, however, showed a positive response to the taurine treatment under ER stress conditions. When C. elegans were treated with taurine before or after the tunicamycin treatment, they showed a less severe level of ER stress, including an enhanced survivorship, increased motility, and augmented fecundity. Taken together, these results strongly indicate that taurine works positively to cope with ER stress from the organismal perspective.
    Full-text · Article · Aug 2010 · Journal of Biomedical Science
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    ABSTRACT: Clearance of misfolded proteins by endoplasmic reticulum (ER)-associated degradation (ERAD) requires concerted activity of chaperones, adaptor proteins, ubiquitin ligases, and proteasomes. RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. Among RNF5-associated proteins is JNK-associated membrane protein (JAMP), a 7-transmembrane protein located within the ER membrane that facilitates degradation of misfolded proteins through recruitment of proteasomes and ERAD regulatory components. Here we demonstrate that RNF5 associates with JAMP in the ER membrane. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97. Consequently, clearance of misfolded proteins, such as CFTRDelta508 and T cell receptor alpha, is less efficient, resulting in their greater accumulation. Significantly, the RNF5 effect on JAMP is seen prior to and after ER stress response, thereby highlighting a novel mechanism to limit ERAD and proteasome assembly at the ER, to the actual ER stress response.
    Preview · Article · Apr 2009 · Journal of Biological Chemistry
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