Intracellular pathogen manipulation of ER-phagy: direct receptor targeting and indirect pathway perturbation

Selective autophagy of the endoplasmic reticulum (ER-phagy) maintains intracellular homeostasis by selectively removing damaged ER membranes and contained misfolded proteins. This review delineates the core molecular mechanisms of canonical autophagy, then systematically describes three types of ER-phagy (macro-ER-phagy, micro-ER-phagy, and vesicular ER-phagy), their signature receptors, subdomain specificities, and regulatory mechanisms, alongside a comparative analysis of the evolutionary divergence between yeast and mammalian ER-phagy receptor systems. At the direct regulation level, diverse intracellular pathogen strategies targeting ER-phagy receptors are examined, including proteasomal degradation and spatial sequestration of FAM134B by viruses, non-canonical micro-ER-phagy hijacking by retroviruses, constitutive antiviral defense mediated by FAM134B against Ebola virus, and bidirectional modulation of this receptor by bacterial effectors and pathogen-associated molecular patterns. At the indirect regulation level, intracellular pathogen-mediated perturbation of upstream nodes-including the UPR, ERAD, ER-RQC/UFMylation, and core macroautophagy machinery-is summarized. These findings underscore the dual role of ER-phagy as both a host defense barrier and a target for pathogen exploitation, providing novel insights into intracellular pathogenic mechanism.