Abstract
The endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome. ER size and content in molecular chaperones increase upon physiologic and pathologic stresses on activation of unfolded protein responses (UPR). On stress resolution, the mammalian ER is remodeled to pre-stress, physiologic size and function on activation of the LC3-binding activity of the translocon component SEC62. This elicits recov-ER-phagy, i.e., the delivery of the excess ER generated during the phase of stress to endolysosomes (EL) for clearance. Here, ultrastructural and genetic analyses reveal that recov-ER-phagy entails the LC3 lipidation machinery and proceeds via piecemeal micro-ER-phagy, where RAB7/LAMP1-positive EL directly engulf excess ER in processes that rely on the Endosomal Sorting Complex Required for Transport (ESCRT)-III component CHMP4B and the accessory AAA+ ATPase VPS4A. Thus, ESCRT-III-driven micro-ER-phagy emerges as a key catabolic pathway activated to remodel the mammalian ER on recovery from ER stress.
Highlights
The endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome
Our studies revealed that SEC62 controls delivery of excess ER to RAB7/LAMP1-positive
Western blot analyses show that the level of ER stress marker proteins increases in wild-type (WT) mouse embryonic fibroblasts (MEFs) exposed to cyclopiazonic acid (CPA) (Fig. 1a, lane 1 vs. 2, upper and middle panels for BiP and HERP, respectively) and decreases after interruption of the pharmacologic treatment[7]
Summary
The endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome. ER size and content in molecular chaperones increase upon physiologic and pathologic stresses on activation of unfolded protein responses (UPR). The mammalian ER is remodeled to pre-stress, physiologic size and function on activation of the LC3-binding activity of the translocon component SEC62 This elicits recov-ER-phagy, i.e., the delivery of the excess ER generated during the phase of stress to endolysosomes (EL) for clearance. ERcentric signals do exist that trigger clearance of select ER subdomains on activation of individual receptors as reported for CCPG1-mediated control of ER expansion during ER stress[10], for SEC62-controlled reduction of the ER volume to physiologic state after conclusions of acute ER stresses[7], and for ER-tolysosome-associated degradation (ERLAD) pathways activated to deliver proteasome-resistant misfolded proteins from the ER to EL for destruction[19,20,21] Acute ER stresses were triggered on transient perturbation of calcium or redox homeostasis to mimic original observation in liver cells showing lysosomal removal of excess ER after cessation of treatments with antiepileptic drugs such as phenobarbital[24,25]
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