title: RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival.
abstract: Although TRAIL is considered a potential anticancer agent, it enhances tumor progression by activating NF-κB in apoptosis-resistant cells. Cellular FLICE-like inhibitory protein (cFLIP) overexpression and caspase-8 activation have been implicated in TRAIL-induced NF-κB activation; however, the underlying mechanisms are unknown. Here, we report that caspase-8-dependent cleavage of RIP1 in the kinase domain (KD) and intermediate domain (ID) determines the activation state of the NF-κB pathway in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. In apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID immediately after the recruitment of RIP1 to the receptor complex, impairing IκB kinase (IKK) recruitment and NF-κB activation. In apoptosis-resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD-cleaved fragment capable of activating NF-κB but not apoptosis. Notably, depletion of the cytoplasmic pool of TRAF2 and cIAP1 in lymphomas by CD40 ligation inhibits basal RIP1 ubiquitination but does not prompt cell death, due to CD40L-induced cFLIP expression and limited RIP1 cleavage. Inhibition of RIP1 cleavage at the KD suppresses NF-κB activation and cell survival even in cFLIP-overexpressing lymphomas. Importantly, RIP1 is constitutively cleaved in human and mouse lymphomas, suggesting that cFLIP-mediated and caspase-8-dependent limited cleavage of RIP1 is a new layer of mechanism that promotes NF-κB activation and lymphoma survival.
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Laiqun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: Interdisciplinary Graduate Program in Molecular and Cellular Biology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Workman
authors.affiliation: Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Songhai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Proteomic Facility, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Pope
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.affiliation: Department of Pathology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA hasem-habelhah@uiowa.edu.
authors.forename: Hasem
authors.initials: H
authors.lastname: Habelhah
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D023201:CD40 Ligand / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism*; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: C119724:AGFG1 protein, human; D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D023201:CD40 Ligand; C505530:CASP8 protein, human; D053181:Caspase 8