Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival.
Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L's physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.
Graduate Program in Biochemistry, Molecular and Cell Biology, Division of Nutritional Sciences, and Department of Animal Science, Cornell University, Ithaca, NY 14853.
Shengyi
S
Sun
Guojun
G
Shi
Xuemei
X
Han
Adam B
AB
Francisco
Yewei
Y
Ji
Nuno
N
Mendonça
Xiaojing
X
Liu
Jason W
JW
Locasale
Kenneth W
KW
Simpson
Gerald E
GE
Duhamel
Sander
S
Kersten
John R
JR
Yates
Qiaoming
Q
Long
Ling
L
Qi
D000818:Animals; D001284:Atrophy; D018929:Cell Culture Techniques; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D060746:Endoplasmic Reticulum-Associated Degradation; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D046790:Pancreas, Exocrine / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D056811:Unfolded Protein Response
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C492169:Sel1h protein, mouse; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
ER dilation; ERAD tuning; exocrine pancreatic insufficiency; inducible ERAD-deficient models; stress granule