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RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival. Mol Cell Biol 2015 Oct;35(19):3324-38



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Pubmed Central ID




Scopus ID

2-s2.0-84941046993 (requires institutional sign-in at Scopus site)   25 Citations


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.

Author List

Zhang L, Blackwell K, Workman LM, Chen S, Pope MR, Janz S, Habelhah H


Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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