Deficiency of Suppressor Enhancer Lin12 1 Like (SEL1L) in Mice Leads to Systemic Endoplasmic Reticulum Stress and Embryonic Lethality

Abstract

Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

“…Variants in the Sel1L gene have been identified in human patients with autoimmune thyroid diseases (34), in canines with progressive early-onset cerebellar ataxia (35), and in humans with Alzheimer's disease (36). However, our ability to dissect physiological roles of Sel1L has been limited because of the embryonic lethality of the Sel1L-deficient mice (11). To circumvent this problem, we have generated and characterized inducible Sel1L-deficient mouse and cell models to permit an assessment of Sel1L function in adult animals and immortalized mouse embryonic fibroblasts (MEFs).…”

Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus

“…their numbers or their morphology. As previous reports have indicated, cells under ER stress or with compromised ER homeostasis often show ER enlargement (31,33,34), suggesting that the ␤ cells of hERO1␤Tg mice were also subjected to ER stress. In fact, the analyses of mRNA expression showed upregulation of the expression of multiple UPR genes in Tg islets, including Bip, Chop, Derl3, and Trb3 (Fig.…”

“…In contrast, we observed evidence of severe ER stress induced by ERO1␤ overexpression. However, despite the upregulation of proapoptotic genes such as Chop or Trb3, as well as the severe dilation of the ER lumen of hERO1␤Tg ␤ cells, which is generally regarded as indicative of unfolded protein accumulation and ER stress (31,33,34), hERO1␤Tg islets did not show evidence of ER stress-induced ␤ cell death; thus, the glucose intolerance of hERO1␤Tg mice was mild and became obvious only after an HFD load. This lack of apoptosis could simply be explained as a consequence of successful compensations achieved through the strongly invoked UPRs, possibly via the downregulation of insulin synthesis, leading to a sort of balanced and maintained status within the ER.…”

Conserved endoplasmic reticulum-associated degradation system to eliminate mutated receptor-like kinases in Arabidopsis

“…A recent study reported that mice homozygous mutant for Sel1L were embryonic lethal because of impaired ERAD and ER homeostasis (41). We suspected that the failure of a null ebs5 mutation on plant growth could be attributable to high folding efficiency of plant secretory and membrane proteins compared with the mammalian systems.…”