TRPV1 SUMOylation suppresses itch by inhibiting TRPV1 interaction with H1 receptors
Yingwei Gao,
Ruining Ma,
Weiji Weng,
Heng Zhang,
Yingping Wang,
Rongjun Guo,
Xiaokun Gu,
Yang Yang,
Fan Yang,
Aiwu Zhou,
Jinke Cheng,
Zhe-Yu Chen,
Michael X. Zhu,
Yong Li
Affiliations
Yingwei Gao
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Ruining Ma
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Weiji Weng
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Heng Zhang
Department of Biophysics and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
Yingping Wang
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Rongjun Guo
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xiaokun Gu
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Yang Yang
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Fan Yang
Department of Biophysics and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
Aiwu Zhou
Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Jinke Cheng
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Zhe-Yu Chen
Institute of Brain Science, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Corresponding author
Michael X. Zhu
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Corresponding author
Yong Li
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, and Faculty of Basic Medicine, Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Corresponding author
Summary: The molecular mechanism underlying the functional interaction between H1R and TRPV1 remains unclear. We show here that H1R directly binds to the carboxy-terminal region of TRPV1 at residues 715–725 and 736–749. Cell-penetrating peptides containing these sequences suppress histamine-induced scratching behavior in a cheek injection model. The H1R-TRPV1 binding is kept at a minimum at rest in mouse trigeminal neurons due to TRPV1 SUMOylation and it is enhanced upon histamine treatment through a transient TRPV1 deSUMOylation. The knockin of the SUMOylation-deficient TRPV1K823R mutant in mice leads to constitutive enhancement of H1R-TRPV1 binding, which exacerbates scratching behaviors induced by histamine. Conversely, SENP1 conditional knockout in sensory neurons enhances TRPV1 SUMOylation and suppresses the histamine-induced scratching response. In addition to interfering with binding, TRPV1 SUMOylation promotes H1R degradation through ubiquitination. Our work unveils the molecular mechanism of histaminergic itch by which H1R directly binds to deSUMOylated TRPV1 to facilitate the transduction of the pruritogen signal to the scratching response.
