A Novel Caspase-2 Complex Containing TRAF2 and RIP1

Jill Demeulemeester,Xavier Saelens,Mohamed Lamkanfi,Wim Declercq,Geertrui Denecker,Michael Kalai,Marjan van Gurp,Kathleen D'hondt,Peter Vandenabeele,Lieselotte Vande Walle

doi:10.1074/jbc.m411180200

Jill Demeulemeester, Xavier Saelens

Open Access

https://doi.org/10.1074/jbc.m411180200

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Abstract

The enzymatic activity of caspases is implicated in the execution of apoptosis and inflammation. Here we demonstrate a novel nonenzymatic function for caspase-2 other than its reported proteolytic role in apoptosis. Caspase-2, unlike caspase-3, -6, -7, -9, -11, -12, and -14, is a potent inducer of NF-kappaB and p38 MAPK activation in a TRAF2-mediated way. Caspase-2 interacts with TRAF1, TRAF2, and RIP1. Furthermore, we demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1. Structure-function analysis shows that NF-kappaB activation occurs independent of enzymatic activity of the protease and that the caspase recruitment domain of caspase-2 is sufficient for the activation of NF-kappaB and p38 MAPK. These results demonstrate the inducible assembly of a novel protein complex consisting of caspase-2, TRAF2, and RIP1 that activates NF-kappaB and p38 MAPK through the caspase recruitment domain of caspase-2 independently of its proteolytic activity.

Highlights

NF-␬B and p38 MAPK activation are involved in the transcriptional activation of numerous inflammation-related and antiapoptotic genes in response to cytokines, bacterial products, and cellular stress conditions [1, 2]
We demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1
These results demonstrate the inducible assembly of a novel protein complex consisting of caspase-2, TRAF2, and RIP1 that activates NF-␬B and p38 MAPK through the caspase recruitment domain of caspase-2 independently of its proteolytic activity

Summary

A Novel Caspase-2 Complex Containing TRAF2 and RIP1*

We demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1. The death domain superfamily includes the death domain (DD), the death effector domain, the caspase recruitment domain (CARD), and the recently identified PYRIN domain [21, 22] Members of this superfamily of homotypic oligomerization domains are involved in both the recruitment of adaptor proteins and the assembly of protein complexes, hereby promoting proteolytic activation of the recruited caspases in the context of apoptosis and inflammation. RIP1, a known substrate of caspase-8 [37, 38], is not cleaved by caspase-2 These results suggest that, in addition to its role in nuclear stress-induced apoptosis, caspase-2 may be involved in proinflammatory pathways through the TRAF2- and RIP1mediated activation of p38 MAPK and NF-␬B

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION