Co-expression of PADI isoforms during progenitor differentiation enables functional diversity.

Protein isoforms, generated through alternative splicing or promoter usage, contribute to tissue function. Here, we characterize the expression of predicted and isoforms in hair follicles and describe expression of , a hitherto unknown PADI2 isoform, in the oligodendrocyte lineage. transcription is initiated from a downstream intronic promoter, generating an N-terminally truncated, unstable, PADI2β. By contrast to the established role of the canonical PADI2 (PADI2α) (Falcao . 2019 . , 1090-1102.e10. (doi:10.1016/j.celrep.2019.03.108)), PADI2β inhibits oligodendrocyte differentiation, suggesting that PADI2 isoforms exert opposing effects on oligodendrocyte lineage progression. We localize and to developing hair follicles and find that both transcripts are expressed at low levels in progenitor cells, only to increase in expression concomitant with differentiation. When expressed , PADI3α and PADI3β are enriched in the cytoplasm and precipitate together. Whereas PADI3β protein stability is low and PADI3β fails to induce protein citrullination, we find that the enzymatic activity and protein stability of PADI3α is reduced in the presence of PADI3β. We propose that PADI3β modulates PADI3α activity by direct binding and heterodimer formation. Here, we establish expression and function of and isoforms, expanding on the mechanisms in place to regulate citrullination in complex tissues. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.