Transient receptor potential channel 1 deficiency impairs host defense and proinflammatory responses to bacterial infection by regulating protein kinase Cα signaling

Xikun Zhou, Yan Ye, Yuyang Sun, Xuefeng Li, Wenxue Wang, Breanna Privratsky, Shirui Tan, Zongguang Zhou, Canhua Huang, Yu Quan Wei, Lutz Birnbaumer, Brij B Singh, Min Wu

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1-/- mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca2+ entry and triggered protein kinase Cα (PKC-α) activity to facilitate nuclear translocation of NF-kB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCγ signaling circuit.

Original languageEnglish (US)
Pages (from-to)2729-2739
Number of pages11
JournalMolecular and Cellular Biology
Volume35
Issue number16
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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