PHPT1/Ocnus negatively regulates the JAK/STAT pathway to control cell survival.

The JAK/STAT signaling pathway is a highly conserved regulator essential for animal development. Here, we show that the Drosophila phosphohistidine phosphatase 1, PHPT1/Ocnus, is required for cell survival by regulating JAK/STAT signaling. Knockdown of ocnus (ocn) leads to apoptosis of germ cells during the transit-amplifying divisions of spermatogonia in the second instar larvae. In Drosophila S2 cells, ocn overexpression reduces phosphorylated STAT (pSTAT) levels, limits its nuclear accumulation, and alters the expression of STAT target genes. Mechanistically, Ocn directly dephosphorylates Stat92E at the conserved tyrosine residue Y711. Consistently, genetic inhibition of JAK/STAT signaling via Socs36E overexpression partially rescues male sterility caused by ocn knockdown. Moreover, human PHPT1 suppresses nuclear accumulation of pSTAT in HeLa cells, indicating evolutionary conservation. Together, our findings identify PHPT1/Ocnus as a conserved negative regulator of JAK/STAT signaling and may provide a potential target for therapeutic intervention in the treatment of STAT-related diseases, including cancer.