PHD3 is a transcriptional coactivator of HIF-1α in nucleus pulposus cells independent of the PKM2-JMJD5 axis

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Zachary R SchoepflinMakarand V Risbud

Abstract

The role of prolyl hydroxylase (PHD)-3 as a hypoxia inducible factor (HIF)-1α cofactor is controversial and remains unknown in skeletal tissues. We investigated whether PHD3 controls HIF-1 transcriptional activity in nucleus pulposus (NP) cells through the pyruvate kinase muscle (PKM)-2-Jumonji domain--containing protein (JMJD5) axis. PHD3-/- mice (12.5 mo old) showed increased incidence of intervertebral disc degeneration with a concomitant decrease in expression of the HIF-1α targets VEGF-A, glucose transporter-1, and lactate dehydrogenase A. PHD3 silencing decreased hypoxic activation of HIF-1α C-terminal transactivation domain (C-TAD), but not HIF-1α-N-terminal-(N)-TAD or HIF-2α-TAD. Moreover, PHD3 suppression in NP cells resulted in decreased HIF-1α enrichment on target promoters and lower expression of select HIF-1 targets. Contrary to other cell types, manipulation of PKM2 and JMJD5 levels had no effect on HIF-1 activity in NP cells. Likewise, stabilization of tetrameric PKM2 by a chemical approach had no effect on PHD3-dependent HIF-1 activity. Coimmunoprecipitation assays showed lack of association between HIF-1α and PKM2 in NP cells. Results support the role of the PHD3 as a cofactor for HIF-1, independent of PKM2-JMJ...Continue Reading

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Citations

Dec 1, 2018·PLoS Biology·Anand R SaranLuciano DiTacchio
Nov 7, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Elizabeth S SilagiMakarand V Risbud
Sep 25, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xingcai CaiGang Shu
May 8, 2020·International Journal of Molecular Sciences·Karel Vališ, Petr Novák
Jun 5, 2021·Nature Reviews. Rheumatology·Elizabeth S SilagiMakarand V Risbud

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