Record Details

Hydrogen sulfide-induced GAPDH sulfhydration disrupts the CCAR2-SIRT1 interaction to initiate autophagy

DIR@IMTECH: CSIR-Institute of Microbial Technology

View Archive Info
 
 
Field Value
 
Title Hydrogen sulfide-induced GAPDH sulfhydration disrupts the CCAR2-SIRT1 interaction to initiate autophagy
 
Creator Iqbal, Iram K.
Bajeli, Sapna
Sahu, Shivani
Bhat, Shabir Ahmed
Kumar, Ashwani
 
Subject QR Microbiology
 
Description The deacetylase SIRT1 (sirtuin 1) has emerged as a major regulator of nucleocytoplasmic distribution of macroautophagy/autophagy marker MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). Activation of SIRT1 leads to the deacetylation of LC3 and its translocation from the nucleus into the cytoplasm leading to an increase in the autophagy flux. Notably, hydrogen sulfide (H2S) is a cytoprotective gasotransmitter known to activate SIRT1 and autophagy; however, the underlying mechanism for both remains unknown. Herein, we demonstrate that H2S sulfhydrates the active site cysteine of the glycolytic enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Sulfhydration of GAPDH leads to its redistribution into the nucleus. Importantly, nuclear localization of GAPDH is critical for H2S-mediated activation of autophagy as H2S does not induce autophagy in cells with GAPDH ablation or cells overexpressing a GAPDH mutant lacking the active site cysteine. Importantly, we observed that nuclear GAPDH interacts with CCAR2/DBC1 (cell cycle activator a nd apoptosis regulator 2) inside the nucleus. CCAR2 interacts with the deacetylase SIRT1 to inhibit its activity. Interaction of GAPDH with CCAR2 disrupts the inhibitory effect of CCAR2 on SIRT1. Activated SIRT1 then deacetylates MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) to induce its translocation into the cytoplasm and activate autophagy. Additionally, we demonstrate this pathway's physiological role in autophagy-mediated trafficking of Mycobacterium tuberculosis into lysosomes to restrict intracellular mycobacteria growth. We think that the pathway described here could be involved in H2S-mediated clearance of intracellular pathogens and other health benefits.
 
Publisher Taylor & Francis
 
Date 2021-02
 
Type Article
PeerReviewed
 
Relation https://www.tandfonline.com/doi/full/10.1080/15548627.2021.1876342
http://crdd.osdd.net/open/2651/
 
Identifier Iqbal, Iram K. and Bajeli, Sapna and Sahu, Shivani and Bhat, Shabir Ahmed and Kumar, Ashwani (2021) Hydrogen sulfide-induced GAPDH sulfhydration disrupts the CCAR2-SIRT1 interaction to initiate autophagy. Autophagy. ISSN 1554-8635