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SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death

Lisa Schlicher1, Manuela Wissler2, Florian Preiss3

  • 1Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University of Freiburg, Freiburg, Germany BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany.

EMBO Reports
|July 27, 2016
PubMed

Insights

SPATA2 interacts with CYLD, an enzyme that regulates TNF receptor signaling. SPATA2 activates CYLD

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumor Necrosis Factor (TNF) receptor signaling involves K63- and Met1-linked ubiquitylation.
  • Deubiquitinases (DUBs), like CYLD, regulate these modifications to control signal strength.
  • The precise regulation of CYLD's activity in TNF signaling is not fully understood.

Purpose of the Study:

  • To identify novel regulators of CYLD in TNF receptor signaling.
  • To elucidate the mechanism by which SPATA2 influences CYLD activity and TNF pathway outcomes.

Main Methods:

  • Mass spectrometry to identify CYLD interaction partners.
  • Co-immunoprecipitation and Western blotting to confirm protein interactions.
  • Analysis of NF-κB and MAPK pathway activation, complex II formation, and apoptosis in response to TNF stimulation.

Main Results:

  • SPATA2 was identified as a CYLD interaction partner, binding via its PUB domain.
  • SPATA2's PUB interaction motif (PIM) binds to the LUBAC component HOIP.
  • SPATA2 is essential for recruiting CYLD to the TNF receptor complex and allosterically activates CYLD's deubiquitinase activity.
  • SPATA2 attenuates TNF-induced NF-κB and MAPK signaling but is required for TNF-induced apoptosis.

Conclusions:

  • SPATA2 is a critical regulator of TNF receptor signaling by modulating CYLD activity.
  • SPATA2 plays a dual role in TNF signaling, inhibiting pro-survival pathways while promoting apoptosis.
  • This discovery highlights SPATA2 as a key factor influencing the diverse effects of TNF.
Keywords:
CYLDHOIPSPATA2TNFapoptosis

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