OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

Nature. 2022 Jul;607(7917):169-175. doi: 10.1038/s41586-022-04842-7. Epub 2022 May 16.

Abstract

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 tumours2,3, particularly as a variant of small-cell lung cancer. Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F3 (refs. 2,4), 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/POU2AF2 and OCA-T2/POU2AF3, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogues of the B-cell-specific coactivator OCA-B; all three proteins are encoded in a gene cluster and contain a conserved peptide that binds to class II POU transcription factors and a DNA octamer motif in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft-cell-like small-cell lung cancer. Moreover, we generated OCA-T1-deficient mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal that the POU2F3-OCA-T complex is the master regulator of tuft cell identity and a molecular vulnerability of tuft-cell-like small-cell lung cancer.

MeSH terms

  • Animals
  • Cell Lineage*
  • Humans
  • Lung Neoplasms* / pathology
  • Mice
  • Mucous Membrane / pathology
  • Multigene Family / genetics
  • Neoplasm Proteins* / metabolism
  • Nucleotide Motifs
  • Octamer Transcription Factors* / metabolism
  • POU Domain Factors / metabolism
  • Small Cell Lung Carcinoma* / pathology
  • Trans-Activators

Substances

  • COLCA2 protein, human
  • Neoplasm Proteins
  • Octamer Transcription Factors
  • POU Domain Factors
  • POU2AF1 protein, human
  • POU2F3 protein, human
  • Trans-Activators
  • POU2AF2 protein, human