MAPK Signaling: Inflammatory Cytokines Pathway

The major output of MAPK signaling downstream of inflammatory cytokines is a proinflammatory response. TNF Receptor (TNFR) activation by TNF superfamily ligands leads to recruitment of TRAF-2, TRAF-3, TRAF-6, and IKK gamma to the TNFR complex. TRAF-2 and TRAF-6 are subsequently auto-polyubiquitinated with Lys63-linked chains in a Ubc13-Uev1a-dependent manner. Ubiquitinated TRAF-2 and TRAF-6 recruit MEKK1 and TAK1, respectively, with TAK1 being recruited via TAB2. TRAF-3 inhibits the activation of MEKK1 and TAK1 at the TNFR complex. cIAP1/2 is then recruited to the TNFR complex and polyubiquitinated with Lys63-linked chains by the Ubc13-Uev1a complex. Ubiquitinated cIAP1/2 then promotes the polyubiquitination of TRAF-3 with Lys48-linked chains, which leads to the degradation of TRAF-3 via the 26S Proteasome. Degradation of TRAF-3 releases the MEKK1 and TAK1 complexes, leading to the activation of MEKK1 and TAK1. MEKK1 and TAK1 subsequently phosphorylate and activate MKK4/7 and MKK3/6, which then phosphorylate JNK and p38, respectively. Activated JNK and p38 translocate to the nucleus where they activate multiple transcription factors, via MSK1/2 in the case of p38, including AP-1, ATF2, CREB, ATF1, and NF-kappa B. The activation of these transcription factors results in the transcription of genes encoding proinflammatory cytokines. In the cytoplasm, the translation of proinflammatory gene mRNA is inhibited by KSRP and TTP, both of which bind to and promote the degradation of mRNA. p38 directly inhibits KSRP and indirectly inhibits TTP, via MAPKAPK2, to promote inflammation via the stabilization and translation of proinflammatory gene mRNA.

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