ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling

Abstract

Background Autophagy and ER stress are involved in maintaining some well-orchestrated mechanisms aimed at either restoring cellular homeostasis or performing cell death. Autophagy is a well-defined process which governs overall cellular stress outcomes. Selective degradation of the ER mediated by autophagy occurs through a specific type of autophagy called ER-phagy, which ensures ER protein homeostasis. Methods Immunoblotting and RT-PCR were used to evaluate the expression of ATG5 and ATG7 in chondrocyte. Western blotting, Flow cytometry,immunofluorescence cell staining and confocal microscope were used to examine the effect of ATG5 and ATG7 on autophagy, ER stress, cell apoptosis and cell proliferation. Transmission electron microscope and confocal microscope were performed to visualize the autophagy flux and autolysosome formation. The role of ATG5 and ATG7 overexpression on the PERK pathway inhibitor were detected by immunoblotting and treatment with inhibitors. Results In current study, we demonstrated that Tm-induced ER stress can activate autophagy while Rapamycin-induced autophagy can inhibit ER stress in chondrocyte. Autophagy related protein ATG5 or ATG7 can promote autophagy and inhibit ER stress individually, and their combined effect can further improve the autophagy enhancement and the ER stress repression. Moreover, ATG5, ATG7 and ATG5 + ATG7 lead cells into more S phase, increase the number of S phase and inhibit apoptosis as well. ATG5, ATG7 and ATG5 + ATG7 regulate autophagy, ER stress, apoptosis and cell cycle through PERK signaling, a vital UPR branch pathway. Conclusions ATG5 and ATG7 connect autophagy with ER stress through PERK signaling. The protective effect of ATG5/7 overexpression on chondrocyte survival relys on PERK signaling. The effect of siPERK and siNrf2 on the cytoprotective effect of ATG5/7 are of synergism, while the effect of siPERK and siATF4 are of antagonism. PERK signal may be the pivot for autophagy, ER homeostasis and ER-phagy in chondrocyte. Electronic supplementary material The online version of this article (10.1186/s12964-019-0353-3) contains supplementary material, which is available to authorized users.

Lactobacillus johnsonii L531 ameliorates enteritis via elimination of damaged mitochondria and suppression of SQSTM1‐dependent mitophagy in a Salmonella infantis model of piglet diarrhea

“…ATG5 forms a complex with ATG12 and is required for autophagosome formation . The ATG5 could increase autolysosome formation and autophagy flux, it could enhance this effect and augment the autolysosome formation in chondrocytes combined with other ATGs under endoplasmic reticulum stress . Deficiency in ATG5 resulted in impaired LC3 recruitment and the resistance of the zebrafish host against S .…”

“…33 The ATG5 could increase autolysosome formation and autophagy flux, it could enhance this effect and augment the autolysosome formation in chondrocytes combined with other ATGs under endoplasmic reticulum stress. 34 Deficiency in ATG5 resulted in impaired LC3 recruitment and the resistance of the zebrafish host against S. typhimurium infection. 35 In addition, downregulation of mRNA levels of ATG5 in brains of scrapie-infected mice has been associated with an impairment of autophagy.…”

The active nuclear form of SREBP1 amplifies ER stress and autophagy via regulation of PERK

“…Protein aggregation in the ER induces the UPR, which entails coordinated recruitment of foldases and export proteins and PERK‐mediated transcriptional block on general protein synthesis. Failure of the UPR to establish protein homeostasis enhances PERK‐mediated apoptotic and autophagic signaling .…”

“…PERK, belonging to the elF2a upstream kinase family, is a type I transmembrane protein also located in the ER . As one of the molecular branches in UPR, PERK and its signaling pathways participate in regulating cell survival and, under sustained activation of the UPR, cell death .…”

AtSec62 is critical for plant development and is involved in ER‐phagy in Arabidopsis thaliana

“…To investigate the regulatory role of AtSec62 under ER stress, we conducted a high‐concentration of TM treatment assay accordingly (Liu et al ; Yang et al ). Both the autophagy related protein ATG5 and ATG7 have been shown to play essential roles in autophagosome formation and ER stress repression, whereas both atg5 and atg7 mutants exhibited the hypersensitive phenotypes under ER stress condition (Yang et al ; Zheng et al ). Therefore, in this study, we also included the atg5 and atg7 mutants (Zhuang et al ) as positive controls for phenotypic responses to TM‐induced ER stress.…”