Deletion of SERP1/RAMP4, a Component of the Endoplasmic Reticulum (ER) Translocation Sites, Leads to ER Stress

Abstract

Stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), also known as ribosome-associated membrane protein 4 (RAMP4), is a Sec61-associated polypeptide that is induced by ER stress. SERP1؊/؊ mice, made by targeted gene disruption, demonstrated growth retardation, increased mortality, and impaired glucose tolerance. Consistent with high levels of SERP1 expression in pancreas, pancreatic islets from SERP1 ؊/؊ mice failed to rapidly synthesize proinsulin in response to a glucose load. In addition, reduced size and enhanced ER stress were observed in the anterior pituitary of SERP1 ؊/؊ mice, and growth hormone production was slowed in SERP1 ؊/؊ pituitary after insulin stimulation. Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1 ؊/؊ pancreas. In basal conditions, the Sec61 complex in SERP1 ؊/؊ microsomes was more cofractionated with ribosomes, compared with SERP1 ؉/؉ counterparts, in high-salt conditions. In contrast, after glucose stimulation, the complex showed less cofractionation at an early phase (45 min) but more at a later phase (120 min). Although intracellular insulin/proinsulin levels were not significantly changed in both genotypes, these results suggest that subtle changes in translocation efficiency play an important role in the regulation of ER stress and rapid polypeptide synthesis.Secretory proteins undergo posttranslational processing, including correct folding and oligomerization, in the endoplasmic reticulum (ER). In order to effectively produce and secrete mature proteins, cellular mechanisms for monitoring the ER environment are essential. In mammalian cells, at least three different mechanisms contribute to this surveillance system: regulated induction of transcription, attenuation of translation, and degradation (11). Exposure of cells to conditions promoting accumulation of unfolded proteins in the ER (ER stress) induces molecular chaperones, folding catalysts, and subunits of the translocation machinery (Sec61 complex), a process known as the unfolded protein response. Attenuation of protein synthesis in response to ER stress provides another point of regulation, in this case serving to reduce the load of proteins entering the ER. The latter pathway requires activation of the ER-resident membrane protein PERK and phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) (5).SERP1 (stress-associated ER protein 1) was identified because of its induction in response to hypoxia or ER stress (20) and found to be identical to RAMP4 (ribosome-associate membrane protein 4). The latter was originally recognized because it was copurified with the Sec61 complex (3, 19) and then found to be a genuine and evolutionarily conserved part of the ER translocon. SERP1/RAMP4 controls glycosylation of major histocompatibility complex class II-associated invariant chains by a translocational pausing mechanism (16), and its overexpression stabilizes newly synthesized membrane proteins under ER stress by ass...

Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA1

“…Interestingly, SERP1 knock-out mice demonstrate growth retardation, increased mortality and impaired insulin response on glucose stimulation (32), phenotypes that are similar to those seen in cell lines with decreased ASNA1 expression (14,16).…”

Molecular effectors and modulators of hypericin-mediated cell death in bladder cancer cells

“…Interestingly, ATF3, a highly PDTinduced stress gene ( Figure 1b, Table 1) encoding a member of the ATF/cAMP-responsive element binding protein family of transcription factors, has been reported to be a PERK target (Jiang et al, 2004), suggesting a link between ATF3 induction and ER stress in our paradigm. PDT also upregulated TRIB3, a downstream negative modulator of the CHOP/ATF4 pathway (Ohoka et al, 2005), the ER protein HER-PUD1 which is involved in ER-associated degradation (ERAD), and SERP1, an ER translocon complex protein (Ma and Hendershot, 2004;Hori et al, 2006).…”

Biogenesis of tail-anchored proteins: the beginning for the end?

“…RAMP4 (ribosome-associated membrane protein 4; also known as SERP1, stress-associated endoplasmic reticulum protein 1) is a Sec61 translocon-associated protein that is upregulated following ER stress (Hori et al, 2006). The protein has a moderately hydrophobic TM segment and is delivered to the ER via an Asna1-mediated route (Favaloro et al, 2008).…”