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

Abstract

Endoplasmic reticulum (ER) stress and autophagy dysfunction contribute to the establishment and progression of diverse pathologies. Proteolytic activation of the transcription factor nSREBP1 is induced under ER stress; however, little is known about how SREBP1 and its nuclear active form nSREBP1 influence autophagy and unfolded protein response (UPR) activation in osteosarcoma cells. Our research focused on the effect of SREBP1/nSREBP1 upon apoptosis and autophagy during ER stress and the molecular mechanisms involved. Here, we showed that nSREBP1 binds to the promoter of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and then regulates ER stress, cell growth, cell apoptosis, and autophagy through the PERK signaling pathway. nSREBP1 increased PERK gene expression and phosphorylation. nSREBP1 was further demonstrated to activate ER stress response through stimulatory effects on PERK signaling. Overexpression of SREBP1 increased its cleavage and release of nSREBP1; therefore, the effect of SREBP1 is achieved through the enhancement of the expression of nSREBP1. Overexpression of SREBP1/nSREBP1 amplifies PERK-associated cell cycle stagnation with G1 phase arresting, S phase reducing, and G2-M phase delaying. LV-SREBP1/nSREBP1 can also bolster PERK's ER stress-associated proapoptotic effects. LV-SREBP1/nSREBP1 and LV-PERK can activate autophagy in ER stress response, along with the overexpression of SREBP1/nSREBP1 and PERK. This resulted in amplification of PERK-related changes to cell proliferation and ER stress-mediated apoptosis and autophagy, with the biological effect of nSREBP1 relying on PERK, which makes up one of the three branches of the UPR signaling pathway. This study reveals important roles for SREBP1/nSREBP1 in PERK signaling under ER stress. Furthermore, nSREBP1, the nuclear active form of SREBP1, is able to robustly augment the effects of PERK. Description of the link between PERK and SREBP1/nSREBP1 function offers an improved understanding of the ER stress response and insight into the biological function of SREBP1/nSREBP1. Abbreviations ATF4, activating transcription factor-4; CHOP, C/EBP-homologous protein; eIF2a, eukaryotic translation initiation factor-2a; ERAD, endoplasmic reticulum-associated protein degradation; ERS, endoplasmic reticulum stress; INSIG1, insulin-induced gene 1; PERK, protein kinase RNA-like endoplasmic reticulum kinase; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBPs, sterol regulatory element-binding proteins; UPR, unfolded protein response.

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