SPOP targets the immune transcription factor IRF1 for proteasomal degradation

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 tumorigenesis, 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 proteasomal turnover. We identified four S/T-rich degrons in IRF1 required for its SPOP MATH domain-dependent turnover. In the absence of SPOP, increased IRF1 protein levels functionally drive increased transcription of IRF1-response-genes, underpinning the biological significance of SPOP in curtailing IRF1 protein abundance.