Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates.
Sophisticated quality control mechanisms prolong retention of protein-folding intermediates in the endoplasmic reticulum (ER) until maturation while sorting out terminally misfolded polypeptides for ER-associated degradation (ERAD). The presence of structural lesions in the luminal, transmembrane, or cytosolic domains determines the classification of misfolded polypeptides as ERAD-L, -M, or -C substrates and results in selection of distinct degradation pathways. In this study, we show that disposal of soluble (nontransmembrane) polypeptides with luminal lesions (ERAD-L(S) substrates) is strictly dependent on the E3 ubiquitin ligase HRD1, the associated cargo receptor SEL1L, and two interchangeable ERAD lectins, OS-9 and XTP3-B. These ERAD factors become dispensable for degradation of the same polypeptides when membrane tethered (ERAD-L(M) substrates). Our data reveal that, in contrast to budding yeast, tethering of mammalian ERAD-L substrates to the membrane changes selection of the degradation pathway.
Bernasconi
Riccardo
R
Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
Galli
Carmela
C
Calanca
Verena
V
Nakajima
Toshihiro
T
Molinari
Maurizio
M
D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D017252:CD3 Complex; C472562:CD3delta antigen; C531192:ERLEC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; D010455:Peptides; D011506:Proteins; D018121:Receptors, Cytokine; C492169:Sel1h protein, mouse; C555000:AMFR protein, human; C555002:Amfr protein, mouse; D060285:Receptors, Autocrine Motility Factor; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases