SPOP targets the immune transcription factor IRF1 for proteasomal degradation

Irene Schwartz, Milica Vunjak, Valentina Budroni, Adriana Cantoran García, Marialaura Mastrovito, Adrian Soderholm, Matthias Hinterndorfer, Melanie de Almeida, Kathrin Hacker, Jingkui Wang, Kimon Froussios, Julian Jude, Thomas Decker, Johannes Zuber, Gijs A. Versteeg (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation of these response proteins after pathogen clearance is likewise key to preventing autoimmunity. Interferon regulatory factor 1 (IRF1) plays an essential role as a transcription factor in driving the expression of immune response genes during infection. The striking difference in functional output with other IRFs is that IRF1 also drives the expression of various cell cycle inhibiting factors, making it an important tumor suppressor. Thus, it is critical to regulate the abundance of IRF1 to achieve a ‘Goldilocks’ zone in which there is sufficient IRF1 to prevent tumor-igenesis, yet not too much which could drive excessive immune activation. Using genetic screening, we identified the E3 ligase receptor speckle type BTB/POZ protein (SPOP) to mediate IRF1 prote-asomal turnover in human and mouse cells. We identified S/T-rich degrons in IRF1 required for its SPOP MATH domain-dependent turnover. In the absence of SPOP, elevated IRF1 protein levels functionally increased IRF1-dependent cellular responses, underpinning the biological significance of SPOP in curtailing IRF1 protein abundance.

OriginalspracheEnglisch
Aufsatznummere89951
FachzeitschrifteLife
Jahrgang12
DOIs
PublikationsstatusVeröffentlicht - 25 Aug. 2023

ÖFOS 2012

  • 106023 Molekularbiologie
  • 106052 Zellbiologie

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