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IP is caused by NF-<jats:italic>\u03ba<\/jats:italic>B essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the I<jats:italic>\u03ba<\/jats:italic>B-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-<jats:italic>\u03ba<\/jats:italic>B response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO. Here we describe that cells expressing the IP-associated NEMO-A323P mutant had completely abrogated TNF-induced NF-<jats:italic>\u03ba<\/jats:italic>B activation, but retained partial antiapoptotic activity and exhibited high sensitivity to death by necroptosis. We found that robust caspase activation in NEMO-deficient cells is concomitant with RIPK3 recruitment to the apoptosis-mediating complex. In contrast, cells expressing the ubiquitin-binding mutant NEMO-A323P did not recruit RIPK3 to complex II, an event that prevented caspase activation. Hence NEMO, independently from NF-<jats:italic>\u03ba<\/jats:italic>B activation, represents <jats:italic>per se<\/jats:italic> a key component in the structural and functional dynamics of the different TNF-R1-induced complexes. Alteration of this process may result in differing cellular outcomes and, consequently, also pathological effects in IP patients with different NEMO mutations.<\/jats:p>","DOI":"10.1038\/cddis.2016.245","type":"journal-article","created":{"date-parts":[[2016,8,25]],"date-time":"2016-08-25T12:48:17Z","timestamp":1472129297000},"page":"e2346-e2346","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II"],"prefix":"10.1038","volume":"7","author":[{"given":"Alessandra","family":"Pescatore","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elio","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Draber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henning","family":"Walczak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matilde Valeria","family":"Ursini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,8,25]]},"reference":[{"key":"BFcddis2016245_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1600-065X.2011.01066.x","volume":"244","author":"H Walczak","year":"2011","unstructured":"Walczak H . 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