title: NEMO regulates a cell death switch in TNF signaling by inhibiting recruitment of RIPK3 to the cell death-inducing complex II.
abstract: Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB 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-κB 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-κB activation, represents per se 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.
authors: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (CNR), Naples 80131, Italy.
authors: Alessandra
authors: A
authors: Pescatore
authors: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (CNR), Naples 80131, Italy.
authors: Elio
authors: E
authors: Esposito
authors: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
authors: Peter
authors: P
authors: Draber
authors: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
authors: Henning
authors: H
authors: Walczak
authors: Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' (CNR), Naples 80131, Italy.
authors: Matilde Valeria
authors: MV
authors: Ursini
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D055786:Gene Knockout Techniques; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; C514981:NEMO protein, mouse; D014409:Tumor Necrosis Factor-alpha; D010768:Phosphoserine; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D051550:I-kappa B Kinase; D020169:Caspases