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RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival
Journal article   Peer reviewed

RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival

Laiqun Zhang, Ken Blackwell, Lauren M Workman, Songhai Chen, Marshall R Pope, Siegfried Janz and Hasem Habelhah
Molecular and cellular biology, Vol.35(19), pp.3324-3338
10/2015
DOI: 10.1128/MCB.00692-15
PMCID: PMC4561725
PMID: 26195820

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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.
 CD40 Ligand - physiology Amino Acid Sequence Cell Survival - drug effects Catalytic Domain Hodgkin Disease - metabolism Jurkat Cells Nuclear Pore Complex Proteins - metabolism Humans Caspase 8 - metabolism Cells, Cultured Molecular Sequence Data Drug Resistance, Neoplasm NF-kappa B - metabolism Mice, Knockout Ubiquitination Animals TNF-Related Apoptosis-Inducing Ligand - pharmacology Proteolysis HEK293 Cells Antineoplastic Agents - pharmacology CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism RNA-Binding Proteins - metabolism

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