TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain

Nat Commun. 2018 Apr 18;9(1):1529. doi: 10.1038/s41467-018-03974-7.

Yan Wang ¹, Yingwei Gao ¹, Quan Tian ², Qi Deng ¹, Yangbo Wang ¹, Tian Zhou ¹, Qiang Liu ², Kaidi Mei ², Yingping Wang ¹, Huiqing Liu ¹, Ruining Ma ¹, Yuqiang Ding ³, Weifang Rong ⁴, Jinke Cheng ¹, Jing Yao ⁵, Tian-Le Xu ⁴, Michael X Zhu ⁶, Yong Li ⁷

Affiliations

1 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China.
3 Department of Anatomy and Neurobiology, Collaborative Innovation Center for Brain Science, Tongji University School of Medicine, 200092, Shanghai, China.
4 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
5 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, China. [email protected].
6 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
7 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].

PMID: 29670121 DOI: 10.1038/s41467-018-03974-7

Abstract

Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund's adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral Infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.

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