The E3 ubiquitin ligase Hectd3 controls immune colonic inflammation by restricting Myd88 signaling

Here we show that deletion of the E3 ubiquitin ligase Hectd3 systemically, or in hematopoietic compartment, including in CD11c+ cells, causes a more severe disease and increased production of proinflammatory cytokines in a murine colitis model. Hectd3 mRNA levels were found reduced in colonic tissues of patients with ulcerative colitis (UC), which highlights a potential role for Hectd3 in regulating inflammatory responses in UC.

We identified Myd88, a central adaptor in the TLR/IL1R signaling and inflammatory response, as a target for Hectd3 ubiquitination. We demonstrate that Hectd3 directly ubiquitinates Myd88 through K27-linked Poly-Ub chains in a nondegradative manner. Hectd3 KO GM-CSF-bone marrow derived cells treated with the TLR4 ligand lipopolysaccharide had increased proinflammatory cytokines, phospho-NF-B and phospho-IRAK4, as well as elevated association of Myd88 with IRAK4, demonstrating that Hectd3 controls Myd88-IRAK4-NF-B axis.