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.
Here, SPATA2 is identified as interaction partner of the deubiquitinase CYLD, mediating its recruitment to the TNF receptor signaling complex, and promoting CYLD activity. SPATA2 is essential for TNFR complex II formation, whereas its loss enhances NF‐κB and MAPK signaling and impairs TNF‐dependent cell death.
SPATA2 interacts with the deubiquitinase CYLD and recruits CYLD to the TNF‐RSC.
SPATA2 enhances the deubiquitinase activity of CYLD.
SPATA2 attenuates NF‐κB and MAPK signaling, but promotes TNF‐induced apoptosis.
- Received April 21, 2016.
- Revision received July 4, 2016.
- Accepted July 5, 2016.
- © 2016 The Authors