Abstract
Toll-like receptor (TLR)-mediated signaling are critical for host defense against pathogen invasion. However, excessive responses would cause harmful damages to the host. Here we show that deficiency of the E3 ubiquitin ligase TRIM32 increases poly(I:C)- and LPS-induced transcription of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines in both primary mouse immune cells and in mice. Trim32-/- mice produced higher levels of serum inflammatory cytokines and were more sensitive to loss of body weight and inflammatory death upon Salmonella typhimurium infection. TRIM32 interacts with and mediates the degradation of TRIF, a critical adaptor protein for TLR3/4, in an E3 activity-independent manner. TRIM32-mediated as well as poly(I:C)- and LPS-induced degradation of TRIF is inhibited by deficiency of TAX1BP1, a receptor for selective autophagy. Furthermore, TRIM32 links TRIF and TAX1BP1 through distinct domains. These findings suggest that TRIM32 negatively regulates TLR3/4-mediated immune responses by targeting TRIF to TAX1BP1-mediated selective autophagic degradation.
Highlights
The innate immune system is the first line of host defense against pathogen invasion
We provide genetic evidence to show that the E3 ubiquitin ligase TRIM32 negatively regulates TLR3/4-mediated innate immune and inflammatory responses
We found that TRIM32-TAX1BP1dependent selective autophagic degradation of the adaptor protein TRIF effectively turned off TLR3/4-mediated innate immune and inflammatory responses
Summary
The innate immune system is the first line of host defense against pathogen invasion. The TIR domains of TLRs mediate their homo- or hetero-dimerization [6], and act as platforms to recruit downstream TIR domain-containing adaptor proteins and other signaling molecules, leading to the activation of transcription factors such as IRF3 and NF-κB. These transcription factors collaborate to induce the transcription of a series of downstream antiviral genes [7]. TLR3, which recognizes viral dsRNA and plays important roles in innate antiviral responses, signals through the TIR-containing adaptor TRIF but not MyD88 [8]. Double knockout of TRIF and MyD88 results in completely abolishment of LPS-induced activation of NF-κB, whereas TRIF-deficiency results in abolishment of LPS-induced activation of IRF3 [9]
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