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MALT 1 cleaves the E3 ubiquitin ligase HOIL ‐1 in activated T cells, generating a dominant negative inhibitor of LUBAC ‐induced NF ‐κB signaling
Author(s) -
Elton Lynn,
Carpentier Isabelle,
Staal Jens,
Driege Yasmine,
Haegman Mira,
Beyaert Rudi
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13597
Subject(s) - ubiquitin ligase , ubiquitin , microbiology and biotechnology , chemistry , signal transduction , nf κb , fusion protein , biology , biochemistry , gene , recombinant dna
Human paracaspase 1 ( PCASP 1), better known as mucosa associated lymphoid tissue lymphoma translocation 1 ( MALT 1), plays a key role in immunity and inflammation by regulating gene expression in lymphocytes and other immune cell types. Deregulated MALT 1 activity has been implicated in autoimmunity, immunodeficiency and certain types of lymphoma. As a scaffold MALT 1 assembles downstream signaling proteins for nuclear factor‐κB ( NF ‐κB) activation, while its proteolytic activity further enhances NF ‐κB activation by cleaving NF ‐κB inhibitory proteins. MALT 1 also processes and inactivates a number of mRNA destabilizing proteins, which further fine‐tunes gene expression. MALT 1 protease inhibitors are currently developed for therapeutic targeting. Here we show that T cell activation, as well as overexpression of the oncogenic fusion protein API 2– MALT 1, induces the MALT 1‐mediated cleavage of haem‐oxidized IRP 2 ubiquitin ligase 1 ( HOIL ‐1). In addition, to acting as a K48‐polyubiquitin specific E3 ubiquitin ligase for different substrates, HOIL ‐1 co‐operates in a catalytic‐independent manner with the E3 ubiquitin ligase HOIL ‐1L interacting protein ( HOIP ) as part of the linear ubiquitin chain assembly complex ( LUBAC ). Intriguingly, cleavage of HOIL ‐1 does not directly abolish its ability to support HOIP ‐induced NF ‐κB signaling, which is still mediated by the N‐terminal cleavage fragment, but generates a C‐terminal fragment with LUBAC inhibitory properties. We propose that MALT 1‐mediated HOIL ‐1 cleavage provides a gain‐of‐function mechanism that is involved in the negative feedback regulation of NF ‐κB signaling.