Off-target inhibition of NGLY1 by the polycaspase inhibitor Z-VAD-fmk induces cellular autophagy.

ABSTRACT: The polycaspase inhibitor Z-VAD-fmk acts as an inhibitor of peptide: N-glycanase (NGLY1), an endoglycosidase which cleaves N-linked glycans from glycoproteins exported from the endoplasmic reticulum (ER) during ER-associated degradation (ERAD). Both pharmacological N-glycanase inhibition by Z-VAD-fmk and siRNA-mediated knockdown (KD) of NGLY1 induce GFP-LC3-positive puncta in HEK 293 cells. The activation of ER stress markers or induction of reactive oxygen species (ROS) is not observed under either condition. Moreover, Ca²⁺ handling is unaffected when observing release from intracellular stores. Under conditions of pharmacological NGLY1 inhibition or NGLY1 KD, upregulation of autophagosome formation without impairment of autophagic flux is observed. Enrichment of autophagosomes

SUBMITTER: Needs SH 

PROVIDER: S-EPMC9304259 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature