A splice variant of the human phosphohistidine phosphatase 1 (PHPT1) is degraded by the proteasome

Int J Biochem Cell Biol. 2014 Dec;57:69-75. doi: 10.1016/j.biocel.2014.10.009. Epub 2014 Oct 14.


Regulation of protein activity by phosphorylation is central in many cellular processes. Phosphorylation of serine, threonine and tyrosine residues is well documented and studied. In addition, other amino acids, like histidine can be phosphorylated, but neither the mechanism nor the function of this modification is well understood. Nevertheless, there is a 14 kDa enzyme with phosphohistidine phosphatase activity, named PHPT1, found in most animals, but not in bacteria, plant or fungi. There are a few splice variant transcripts formed from the human PHPT1 locus and some of them are predicted to form variant proteins, but studies of these proteins are lacking. In order to get insight into the possible function of the variant transcripts encoded at the PHPT1 locus, ectopic expression of PHPT1 transcript variant 6, predicted to be degraded by the non-sense mediated mRNA decay pathway, in HeLa cells was undertaken. In HeLa cells the splice variant protein was degraded by the proteasome, unlike the wild type protein. Using an in silico modeling approach the variant C-terminal end of the proteins were predicted to form different secondary structures that might explain the different properties of the two proteins. The specific degradation of the PHPT1 splice variant indicates that at least for the PHPT1 protein, the quality control and the self-guarding of the cellular system works at two levels, first at the RNA level, aberrant transcripts are degraded by the non-sense mediated mRNA decay pathway, and the small amount of proteins that are formed will be degraded by the proteasome.

Keywords: Nonsense-mediated decay; PHPT1; Phosphohistidine phosphatase; Proteasome; Splice variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cullin Proteins / metabolism
  • HeLa Cells
  • Humans
  • Isoenzymes
  • Molecular Sequence Data
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Structure, Secondary
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Structure-Activity Relationship
  • Transfection


  • CUL5 protein, human
  • Cullin Proteins
  • Isoenzymes
  • RNA, Messenger
  • PHPT1 protein, human
  • Phosphoric Monoester Hydrolases
  • Proteasome Endopeptidase Complex