SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association.
Yun-Hong HuYang WangFei WangYan-Ming DongWan-Ling JiangYa-Ping WangXing ZhongLi-Xin MaPublished in: Cellular & molecular immunology (2020)
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.
Keyphrases
- toll like receptor
- nuclear factor
- inflammatory response
- immune response
- oxidative stress
- signaling pathway
- lps induced
- genome wide
- dendritic cells
- dna methylation
- transcription factor
- gene expression
- bone marrow
- cell proliferation
- epithelial mesenchymal transition
- weight gain
- single cell
- endoplasmic reticulum stress
- copy number
- drug induced