Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects

Ru Yang; Yun Gao; Hui Li; Wei Huang; Dezhen Tu; Mengnan Yang; Xingqian Liu; Jau-Shyong Hong; Hui-Ming Gao

doi:10.1016/j.celrep.2022.111330

Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects

Cell Rep. 2022 Sep 13;40(11):111330. doi: 10.1016/j.celrep.2022.111330.

Authors

Ru Yang¹, Yun Gao², Hui Li¹, Wei Huang¹, Dezhen Tu², Mengnan Yang¹, Xingqian Liu¹, Jau-Shyong Hong³, Hui-Ming Gao⁴

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Institute for Brain Sciences, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing, Jiangsu Province 210023, China.
² State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Institute for Brain Sciences, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing, Jiangsu Province 210023, China; Laboratory of Neurobiology, National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
³ Laboratory of Neurobiology, National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, Ministry of Education Key Laboratory of Model Animal for Disease Study, Institute for Brain Sciences, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing, Jiangsu Province 210023, China. Electronic address: gaohm@nju.edu.cn.

Abstract

Nuclear protein high-mobility group box 1 (HMGB1) can be actively secreted by activated immune cells and functions as a proinflammatory cytokine. Regulation of HMGB1 secretion is critical for treatment of HMGB1-mediated inflammation and related diseases. This study demonstrates that S-nitrosylation (SNO; the covalent binding of nitric oxide [NO] to cysteine thiols) by inducible nitric oxide synthase (iNOS)-derived NO at Cys106 is essential and sufficient for inflammation-elicited HMGB1 secretion. iNOS deletion or inhibition or Cys106Ser mutation prevents lipopolysaccharide (LPS)- and/or poly(I:C)-elicited HMGB1 secretion. NO donors induce SNO of HMGB1 and reproduce inflammogen-triggered HMGB1 secretion. SNO of HMGB1 promotes its proinflammatory and neurodegenerative effects. Intranigral HMGB1 injection induces chronic microglial activation, dopaminergic neurodegeneration, and locomotor deficits, the key features of Parkinson's disease (PD), in wild-type, but not Mac1 (CD11b/CD18)-deficient, mice. This study indicates pivotal roles for SNO modification in HMGB1 secretion and HMGB1-Mac1 interaction for inflammatory neurodegeneration, identifying a mechanistic basis for PD development.

Keywords: CP: Immunology; CP: Neuroscience; HMGB1; Mac1; Parkinson’s disease; S-nitrosylation; iNOS; macrophages; microglia; neurodegeneration; neuroinflammation; nitric oxide.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

Animals
HMGB1 Protein / metabolism*
Inflammation
Lipopolysaccharides / pharmacology
Mice
Nitric Oxide / metabolism
Nitric Oxide Donors

Substances

HMGB1 Protein
HMGB1 protein, mouse
Lipopolysaccharides
Nitric Oxide Donors
Nitric Oxide

Grants and funding

Z01 ES090082/ImNIH/Intramural NIH HHS/United States