Editors' ChoicePosttranslational Modifications

Limiting T cell histidine phosphorylation

Sci. Signal.  16 Aug 2016:
Vol. 9, Issue 441, pp. ec185
DOI: 10.1126/scisignal.aai7941

The availability of reagents has determined the types of posttranslational modifications that can be studied. The ability to study protein histidine phosphorylation in mammalian cells has benefited from the development of antibodies that recognize proteins phosphorylated at the nitrogen at the 1 position of the imidazole ring of histidine or the nitrogen at the 3 position. Panda et al. identified phosphoglycerate mutase 5 (PGAM5) as an interacting partner of the histidine kinase nucleoside diphosphate kinase B (NDPK-B) in HEK 293T cells and showed that the long form of PGAM5 dephosphorylated NDPK-B in vitro through a process involving the transfer of phosphate from NDPK-B to His105 of PGAM5. In T cells, histidine phosphorylation of the calcium-activated K+ channel KCa3.1 by NDPK-B contributes to calcium influx by maintaining the electrical gradient. Whereas the phosphatase PHPT-1 dephosphorylates KCa3.1, genetic knockout or knocking down PGAM5 in primary mouse or human T cells enhanced NDPK-B histidine phosphorylation at the 1 position and KCa3.1 histidine phosphorylation at the 3 position, increased T cell receptor–stimulated calcium influx, and enhanced proinflammatory cytokine production. Compared with transfer of T cells from wild-type mice, allogeneic transfer of T cells from Pgam5-knockout mice produced more severe graft-versus-host disease, which was associated with increased proinflammatory cytokines in the circulation of the recipient mice. Thus, rather than dephosphorylating the target proteins directly, PGAM5 limits histidine phosphorylation by preventing phosphotransfer from the histidine kinase (NDPK-B) to its targets, thereby regulating this posttranslational modification that is important for setting the threshold for T cell activation.

S. Panda, S. Srivastava, Z. Li, M. Vaeth, S. R. Fuhs, T. Hunter, E. Y. Skolnik, Identification of PGAM5 as a mammalian protein histidine phosphatase that plays a central role to negatively regulate CD4+ T cells. Mol. Cell 63, 457–469 (2016). [PubMed]