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
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Additional Information: | The copyright of this article belongs to T&F. |
| Uncontrolled Keywords: | Autophagy;CCAR2;GAPD;Hhydrogen sulfide;Mycobacterium tuberculosis;PRKAA;SIRT1;starvation;sulfhydration;tuberculosis |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 25 Feb 2021 04:16 |
| Last Modified: | 22 Jun 2021 05:18 |
| URI: | http://crdd.osdd.net/open/id/eprint/2651 |
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