Abstract
Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses.
Highlights
Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play central roles in pathogen recognition and elimination.[1]
We found that speckle-type POZ protein (SPOP) acted in the cytoplasm in the TLR4-mediated signaling pathway
Knockdown of SPOP increased IL-1β-induced production of inflammatory cytokines. These results suggest that SPOP negatively regulates TLR- or IL-1Rmediated inflammatory cytokine expression through the MyD88dependent pathway
Summary
Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play central roles in pathogen recognition and elimination.[1] TLRs have a conserved cytoplasmic signaling Toll/IL-1R (TIR) domain. Binding of pathogen-associated molecular patterns to a TLR triggers innate immune responses through the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway and/or TIR-domain-containing adapter-inducing interferon-β(TRIF)-dependent pathway and initiates downstream signaling events that lead to the production of proinflammatory cytokines and type I interferons (IFNs).[2,3,4]. Formation of a myddosome leads to the activation of tumor necrosis factor receptor-associated factor 6 (TRAF6).[6,8,9,10] TRAF6 further mediates the activation of NF-κB and induction of inflammatory genes.[11] TLR3 transduces signals through TRIF.[12] TLR4 is the only receptor that signals through MyD88 to activate NF-κB and TRIF, which activate both NF-κB and IRF3.13–15 TLRs are essential for the elicitation of protective immune responses against infection, inappropriate TLR responses contribute to chronic inflammation and/or autoimmune diseases. Precise control of TLR signaling is critical for maintaining immune homeostasis
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