Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft cell-like human tumors2,3, particularly as a variant form of small cell lung cancer (SCLC). Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F32,4, although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1 and OCA-T2, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogs of the B cell-specific coactivator OCA-B, which are encoded in a gene cluster and harbor a conserved peptide that binds to class II POU transcription factors and octamer motif DNA in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft cell-like SCLC. In addition, we generated OCA-T1 knockout mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal the POU2F3-OCA-T complex as the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft cell-like SCLC.

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