2. Academic Validation
  3. VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2

VCPIP1 potentiates innate immune responses by non-catalytically reducing the ubiquitination of IRAK1/2

  • Cell Rep. 2025 Jul 22;44(7):115931. doi: 10.1016/j.celrep.2025.115931.
Liyan Lou 1,  Jiangyun Shen 1,  Jianzhao Zhang 1,  Fuqi Mei 1,  Deyu Deng 1,  Deqi Wang 2,  Yanqi Xu 1,  Kangmin Chen 1,  Baoli Cheng 3,  Jinghua Liu 4,  Xu Wang 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China.
  • 2 The First School of Medicine and School of Information and Engineering, Wenzhou Medical University, Wenzhou 325035, China.
  • 3 Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 4 Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 5 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou 325000, China. Electronic address: sunrim@163.com.
PMID: 40581931 DOI: 10.1016/j.celrep.2025.115931
Abstract

The host innate immune system is efficiently activated after recognizing microbial components, such as lipopolysaccharide (LPS), by Toll-like receptors (TLRs). However, the molecular basis for the regulation of TLR-mediated signaling remains poorly understood. Here, we report that valosin containing protein interacting protein 1 (VCPIP1), a deubiquitinating enzyme, acts as a critical positive regulator of TLR4 signaling. TLR4 activation induces the upregulation and nuclear-to-cytoplasmic translocation of VCPIP1. The cytoplasmic VCPIP1 interacts with interleukin-1 receptor-associated kinase 1 and 2 (IRAK1/2) and maintains IRAK1/2 protein levels by reducing their degradation through the ubiquitin-proteasome system. Instead of directly deubiquitinating IRAK1/2 through the enzymatic activity, VCPIP1 blocks the K48 ubiquitination of IRAK1/2 in a non-catalytic manner. Ablation of VCPIP1 significantly attenuates LPS-induced inflammatory gene expression in macrophages. Consistently, VCPIP1-deficient mice are less susceptible to sepsis. Thus, this work reveals an essential role of VCPIP1 in TLR4 signaling and suggests that VCPIP1 may become a potential therapeutic target for inflammatory diseases.

Keywords

CP: Cell biology; CP: Immunology; VCPIP1; innate immune response; sepsis; signal transduction; ubiquitination.

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