Segregation and rapid turnover of EDEM1 by an autophagy-like mechanism modulates standard ERAD and folding activities.
EDEM1 is a crucial regulator of endoplasmic reticulum (ER)-associated degradation (ERAD) that extracts non-native glycopolypeptides from the calnexin chaperone system. Under normal growth conditions, the intralumenal level of EDEM1 must be low to prevent premature interruption of ongoing folding programs. We report that in unstressed cells, EDEM1 is segregated from the bulk ER into LC3-I-coated vesicles and is rapidly degraded. The rapid turnover of EDEM1 is regulated by a novel mechanism that shows similarities but is clearly distinct from macroautophagy. Cells with defective EDEM1 turnover contain unphysiologically high levels of EDEM1, show enhanced ERAD activity and are characterized by impaired capacity to efficiently complete maturation of model glycopolypeptides. We define as ERAD tuning the mechanisms operating in the mammalian ER at steady state to offer kinetic advantage to folding over disposal of unstructured nascent chains by selective and rapid degradation of ERAD regulators.
Calì
Tito
T
Institute for Research in Biomedicine, Protein Folding and Quality Control, Via V. Vela 6, CH-6500 Bellinzona, Switzerland.
Galli
Carmela
C
Olivari
Silvia
S
Molinari
Maurizio
M
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D017510:Protein Folding; D017384:Sequence Deletion
C502778:ATG5 protein, human; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C486654:EDEM1 protein, human; C434526:Edem1 protein, mouse; D006023:Glycoproteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins