G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity.

Autor:	Pramanick A; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Chakraborti S; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Mahata T; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Basak M; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Das K; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Verma SK; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Sengar AS; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Singh PK; Department of Surgery, Millers School of Medicine, University of Miami, Miami, FL, 33136, USA., Kumar P; Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India., Bhattacharya B; Department of Pharmacy, Geethanjali College of Pharmacy, Cheeryala, Keesara(M), Rangareddy District, Telangana, 501301, India., Biswas S; Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India., Pal PB; Department of Forensic Medicine, College of Medicine and Sagore Dutta Hospital, B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India., Sarkar S; Department of Surgery, College of Medicine and Sagore Dutta Hospital, B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India., Agrawal V; Department of Pathology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow, Uttar Pradesh, 226014, India., Saha S; Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India., Nath D; Department of Zoology, University of Kalyani, Nadia, West Bengal, 741235, India., Chatterjee S; Department of Biotechnology, Anna University and Vascular Biology Laboratory, AU-KBC Research Centre, MIT Campus, Chennai, 600044, India., Stewart A; Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA., Maity B; Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India. Electronic address: bmaity@cbmr.res.in.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2021 Jul; Vol. 43, pp. 101965. Date of Electronic Publication: 2021 Apr 28.
DOI:	10.1016/j.redox.2021.101965
Abstrakt:	Excessive ingestion of the common analgesic acetaminophen (APAP) leads to severe hepatotoxicity. Here we identify G protein β5 (Gβ 5 ), elevated in livers from APAP overdose patients, as a critical regulator of cell death pathways and autophagic signaling in APAP-exposed liver. Liver-specific knockdown of Gβ 5 in mice protected the liver from APAP-dependent fibrosis, cell loss, oxidative stress, and inflammation following either acute or chronic APAP administration. Conversely, overexpression of Gβ 5 in liver was sufficient to drive hepatocyte dysfunction and loss. In hepatocytes, Gβ 5 depletion ameliorated mitochondrial dysfunction, allowed for maintenance of ATP generation and mitigated APAP-induced cell death. Further, Gβ 5 knockdown also reversed impacts of APAP on kinase cascades (e.g. ATM/AMPK) signaling to mammalian target of rapamycin (mTOR), a master regulator of autophagy and, as a result, interrupted autophagic flux. Though canonically relegated to nuclear DNA repair pathways, ATM also functions in the cytoplasm to control cell death and autophagy. Indeed, we now show that Gβ 5 forms a direct, stable complex with the FAT domain of ATM, important for autophosphorylation-dependent kinase activation. These data provide a viable explanation for these novel, G protein-independent actions of Gβ 5 in liver. Thus, Gβ 5 sits at a critical nexus in multiple pathological sequelae driving APAP-dependent liver damage. (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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