| First Author | Zilberman-Rudenko J | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 6 | Pages | 1612-7 |
| PubMed ID | 26802121 | Mgi Jnum | J:230498 |
| Mgi Id | MGI:5762721 | Doi | 10.1073/pnas.1518163113 |
| Citation | Zilberman-Rudenko J, et al. (2016) Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-kappaB activation and autoinflammatory disease. Proc Natl Acad Sci U S A 113(6):1612-7 |
| abstractText | Receptor-induced NF-kappaB activation is controlled by NEMO, the NF-kappaB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (DeltaCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IkappaB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, DeltaCT-NEMO mutants promoted increased NF-kappaB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-kappaB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-kappaB activation by NEMO, and its absence results in autoinflammatory disease. |
