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SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1.

ABSTRACT:

Abbreviations

aa: amino acid; ATF6: activating transcription factor 6; ATG5: autophagy related 5; CCPG1: cell cycle progression 1; CFTR: CF transmembrane conductance regulator; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HSV-1: herpes simplex virus type 1; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNB1/IFN-β: interferon beta 1; IRF3: interferon regulatory factor 3; ISG15: ISG15 ubiquitin like modifier; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; NFKB/NF-κB: nuclear factor kappa B; NSP6: non-structural protein 6; Δ106-108: deletion of amino acids 106-108 in NSP6 of SARS-CoV-2; Δ105-107: deletion of amino acids 105-107 in NSP6 of SARS-CoV-2; RETREG1/FAM134B: reticulophagy regulator 1; RIGI/DDX58: RNA sensor RIG-I; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

SUBMITTER: Jiao P

PROVIDER: S-EPMC10621274 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1.

Jiao Pengtao P Fan Wenhui W Ma Xiaoya X Lin Runshan R Zhao Yuna Y Li Yabo Y Zhang He H Jia Xiaojuan X Bi Yuhai Y Feng Xiaoli X Li Minghua M Liu Wenjun W Zhang Ke K Sun Lei L

Autophagy 20230723 12

<h4>Abbreviations</h4>aa: amino acid; ATF6: activating transcription factor 6; ATG5: autophagy related 5; CCPG1: cell cycle progression 1; CFTR: CF transmembrane conductance regulator; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to ...[more]

PMID: 37482689

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Project description:BackgroundXanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known.MethodsThe effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope.ResultsMechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity.ConclusionsCollectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.

Dataset Information

SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1.

Abbreviations

Publications

SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1.

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