A noncanonical cytoplasmic role for BUB1 in restraining DNA damage-induced dsRNA accumulation and sensing within stress granules.

Abstract

Budding uninhibited by benzimidazoles 1 (BUB1) is a nuclear serine/threonine protein kinase that ensures proper chromosome segregation before mitosis. We report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and the ensuing immune response. Tumors deficient in BUB1 were sensitive to radiotherapy in a CD8 T cell-dependent manner. We found increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS dsRNA-sensing pathway. Mechanistically, we found that after radiation exposure, BUB1 underwent nucleus-to-cytoplasm migration, where it bound and phosphorylated the poly(A)-binding protein PABPC1, which was degraded together with its associated messenger RNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response.