Bifunctional protein PCBD2 operates as a co‐factor for hepatocyte nuclear factor 1β and modulates gene transcription.

Lotte Tholen, Jeroen de Baaij and colleagues from theme Renal disorders, published in the FASEB Journal that PCBD1 and PCBD2 exert different effects on HNF1β‐mediated transcription. The project is funded by the Dutch Kidney Foundation.

Hepatocyte nuclear factor 1β (HNF1β) is an essential transcription factor in development of the kidney, liver, and pancreas. HNF1β‐mediated transcription of target genes is dependent on the cell type and the development stage. Nevertheless, the regulation of HNF1β function by enhancers and co‐factors that allow this cell‐specific transcription is largely unknown. 

To map the HNF1β interactome we performed mass spectrometry in a mouse kidney inner medullary collecting duct cell line. Pterin‐4a‐carbinolamine dehydratase 2 (PCBD2) was identified as a novel interaction partner of HNF1β. PCBD2 and its close homolog PCBD1 shuttle between the cytoplasm and nucleus to exert their enzymatic and transcriptional activities. Although both PCBD proteins share high sequence identity (48% and 88% in HNF1 recognition helix), their tissue expression patterns are unique. PCBD1 is most abundant in kidney and liver while PCBD2 is also abundant in lung, spleen, and adipose tissue. 

Using immunolocalization studies and biochemical analysis we show that in presence of HNF1β the nuclear localization of PCBD1 and PCBD2 increases significantly. Promoter luciferase assays demonstrate that co‐factors PCBD1 and PCBD2 differentially regulate the ability of HNF1β to activate the promoters of transcriptional targets important in renal electrolyte homeostasis. Deleting the N‐terminal sequence of PCBD2, not found in PCBD1, diminished the differential effects of the co‐factors on HNF1β activity. 

All together these results indicate that PCBD1 and PCBD2 can exert different effects on HNF1β‐mediated transcription. Future studies should confirm whether these unique co‐factor activities also apply to HNF1β‐target genes involved in additional processes besides ion transport in the kidney.

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