SPATA2 Promotes CYLD Activity and Regulates TNF-induced NF-κB Signaling and Cell Death

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2016 Jul 27

PMID 27458237

Citations 68

Authors

Lisa Schlicher

Manuela Wissler

Florian Preiss

Prisca Brauns-Schubert

Celia Jakob

Veronica Dumit

Christoph Borner

Joern Dengjel

Ulrich Maurer

Affiliations

Soon will be listed here.

Abstract

K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely understood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimulation. Moreover, SPATA2 acts as an allosteric activator for the K63- and M1-deubiquitinase activity of CYLD In consequence, SPATA2 substantially attenuates TNF-induced NF-κB and MAPK signaling. Conversely, SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis. Thus, this study identifies SPATA2 as an important factor in the TNF signaling pathway with a substantial role for the effects mediated by the cytokine.

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