Dataset Information

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

ABSTRACT: Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1β receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (H₂S) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular H₂S ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway.

SUBMITTER: Li M

PROVIDER: S-EPMC9030249 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

Li Meng M Hu Wei W Wang Ran R Li Zhaoyi Z Yu Yue Y Zhuo Yue Y Zhang Yida Y Wang Zhou Z Qiu Yuanye Y Chen Keyuan K Ding Qian Q Qi Wei W Zhu Menglin M Zhu Yizhun Y

Antioxidants (Basel, Switzerland) 20220407 4

Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1β receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumat ...[more]

PMID: 35453416

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Project 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.Abbreviations: ATG5: autophagy related 5; ATG7: autophagy related 7; BECN1: beclin 1, autophagy related; CCAR2/DBC1: cell cycle activator and apoptosis regulator 2; CFU: colony-forming units; DLG4/PSD95: discs large MAGUK scaffold protein 4; EX-527: 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H2S: hydrogen sulfide; HEK: human embryonic kidney cells; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; MOI: multiplicity of infection; NO: nitric oxide; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PLA: proximity ligation assay; PRKAA: protein kinase, AMP-activated, alpha catalytic subunit; SIAH1: siah E3 ubiquitin protein ligase 1A; SIRT1: sirtuin 1; TB: tuberculosis; TP53INP2/DOR: transformation related protein 53 inducible nuclear protein 2; TRP53/TP53: transformation related protein 53.

Dataset Information

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

Publications

Sp1 S-Sulfhydration Induced by Hydrogen Sulfide Inhibits Inflammation via HDAC6/MyD88/NF-κB Signaling Pathway in Adjuvant-Induced Arthritis.

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