Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Genetics Program, Stony Brook University, Stony Brook, NY, USA.
Nature. 2022 Jul;607(7917):169-175. doi: 10.1038/s41586-022-04842-7. Epub 2022 May 16.
Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues. Recent studies have also revealed tuft-cell-like human tumours, 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. ), 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.
类锥体细胞是一种罕见的化学感觉谱系，它协调粘膜组织中针对外来病原体的免疫和神经反应。最近的研究还揭示了类锥体细胞样的人类肿瘤，特别是作为小细胞肺癌的一种变体。正常和肿瘤类锥体细胞都共享转录因子 POU2F3 的遗传需求（参考文献），尽管产生这种细胞类型的转录机制还了解甚少。在这里，我们表明 POU2F3 与未被描述的蛋白质 C11orf53 和 COLCA2（在这里分别重新命名为 OCA-T1/POU2AF2 和 OCA-T2/POU2AF3）的结合对于类锥体细胞谱系是至关重要的。OCA-T1 和 OCA-T2 是 B 细胞特异性共激活因子 OCA-B 的旁系同源物；这三种蛋白质都编码在一个基因簇中，包含一个保守的肽段，该肽段以二价的方式结合 II 类 POU 转录因子和 DNA 八聚体基序。我们证明 POU2F3 与 OCA-T1 或 OCA-T2 之间的结合对于类锥体细胞样小细胞肺癌是必不可少的。此外，我们生成了 OCA-T1 缺陷型小鼠，这些小鼠虽然存活，但在几种粘膜组织中缺乏类锥体细胞。这些发现揭示了 POU2F3-OCA-T 复合物是类锥体细胞特性的主调节因子，也是类锥体细胞样小细胞肺癌的分子脆弱性。
