The NPR/Hal family of protein kinases in yeasts: biological role, phylogeny and regulation under environmental challenges

The Hrk1 kinase is a determinant of acetic acid tolerance in yeast by modulating H+ and K+ homeostasis

“…Hrk1 is an important determinant of acetic acid tolerance and a member of the NPR/Hal family of kinases [ 13 , 15 ]. These yeast-specific kinases have been implicated in the modulation of fundamental biological processes, primarily through the regulation of plasma membrane proteins involved in nutrient uptake and metabolism, ion homeostasis, and tolerance to environmental stresses (reviewed in [ 15 ]). Two phosphoproteomics analyses have suggested several potential targets for the activity of the Hrk1 protein kinase [ 16 , 17 ].…”

“…The gene PMA1 encodes the major form of yeast plasma membrane H + -ATPase being the first biological target attributed to Hrk1 [ 21 ]. Although Hrk1 was reported to be involved in the mild glucose-activation of this proton pump, the impact of Ptk2, a kinase belonging to the same family as Hrk1, is substantially higher [ 15 , 21 ]. Pma1 is an essential enzyme for yeast physiology, as a null mutation in haploid cells is lethal [ 22 ].…”

“…One of the main effectors is the transcription factor Haa1, which is responsible for the direct or indirect transcriptional activation of 80% of acetic acid-responsive genes, including the gene encoding the Hrk1 kinase [12][13][14]. Hrk1 is an important determinant of acetic acid tolerance and a member of the NPR/Hal family of kinases [13,15]. These yeast-specific kinases have been implicated in the modulation of fundamental biological processes, primarily through the regulation of plasma membrane proteins involved in nutrient uptake and metabolism, ion homeostasis, and tolerance to environmental stresses (reviewed in [15]).…”

The role of ion homeostasis in adaptation and tolerance to acetic acid stress in yeasts

“…Specific yeast protein kinases play an instrumental role in the activation of Pma1 through phosphorylation. The protein kinase Hrk1 is a major acetic acid stress tolerance determinant in yeast (Antunes et al 2018 , 2023 , Mira et al 2010b , Bernardo et al 2017 , Guerreiro et al 2017 , Xu et al 2019a ), belonging to the NPR/Hal family (Antunes and Sá-Correia 2022 ). Under acetic acid stress conditions, Hrk1 contributes to the phosphorylation of Pma1 residues Ser911 and Thr912 (Guerreiro et al 2017 ), whereas in response to glucose metabolism the kinases Ptk1 and Ptk2 act both in a largely redundant manner in mediating the phosphorylation of Ser911 and Thr912, with Ptk2 promoting the double phosphorylation more efficiently than Ptk1 (Guarini et al 2024 ).…”

“…Under nonstressing conditions, it occurs mainly at the post-translational level through phosphorylation, with several key players contributing to its activity and stability. Notably, the kinases Hal4 and Hal5, from the Npr/Hal family (Antunes and Sá-Correia 2022 ), are known for stabilizing Trk1 at the plasma membrane by phosphorylating its C-terminal end, a process that also involves the activity of the kinase Snf1 (Portillo et al 2005 , Pérez-Valle et al 2007 , Casado et al 2010 ). The Snf1 kinase is notable for its influence on the activity of the Trk system (Portillo et al 2005 ).…”