title: Decreased linear ubiquitination of NEMO and FADD on apoptosis with caspase-mediated cleavage of HOIP.
abstract: NF-κB is crucial to regulate immune and inflammatory responses and cell survival. LUBAC generates a linear ubiquitin chain and activates NF-κB through ubiquitin ligase (E3) activity in the HOIP subunit. Here, we show that HOIP is predominantly cleaved by caspase at Asp390 upon apoptosis, and that is subjected to proteasomal degradation. We identified that FADD, as well as NEMO, is a substrate for LUBAC. Although the C-terminal fragment of HOIP retains NF-κB activity, linear ubiquitination of NEMO and FADD decreases upon apoptosis. Moreover, the N-terminal fragment of HOIP binds with deubiquitinases, such as OTULIN and CYLD-SPATA2. These results indicate that caspase-mediated cleavage of HOIP divides critical functional regions of HOIP, and that this regulates linear (de)ubiquitination of substrates upon apoptosis.
authors.affiliation: Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Goto
authors.affiliation: Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan. Electronic address: ftokunaga@med.osaka-cu.ac.jp.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000276:immunology / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000276:immunology / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism*; D019169:Jurkat Cells; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C491731:IKBKG protein, human; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase; D020169:Caspases
keywords: Apoptosis; Caspase; Deubiquitinase; NF-κB; Ubiquitin