Crosstalk between protein kinase A and the HOG pathway under impaired biosynthesis of complex sphingolipids in budding yeast

Abstract

Complex sphingolipids are important components of the lipid bilayer of budding yeast Saccharomyces cerevisiae, and a defect of the biosynthesis causes widespread cellular dysfunction. In this study, we found that mutations causing upregulation of the cAMP/protein kinase A (PKA) pathway cause hypersensitivity to the defect of complex sphingolipid biosynthesis caused by repression of AUR1 encoding inositol phosphorylceramide synthase, whereas loss of PKA confers resistance to the defect. Loss of PDE2 encoding cAMP phosphodiesterase or PKA did not affect the reduction in complex sphingolipid levels and ceramide accumulation caused by AUR1 repression, suggesting that the change in sensitivity to the AUR1 repression due to the mutation of the cAMP/PKA pathway is not caused by exacerbation or suppression of the abnormal metabolism of sphingolipids. We also identified PBS2 encoding MAPKK in the high‐osmolarity glycerol (HOG) pathway as a multicopy suppressor gene that rescues the hypersensitivity to AUR1 repression caused by deletion of IRA2, which causes hyperactivation of the cAMP/PKA pathway. Since the HOG pathway has been identified as one of the rescue systems against the growth defect caused by the impaired biosynthesis of complex sphingolipids, it was assumed that PKA affects activation of the HOG pathway under AUR1‐repressive conditions. Under AUR1‐repressive conditions, hyperactivation of PKA suppressed the phosphorylation of Hog1, MAPK in the HOG pathway, and transcriptional activation downstream of the HOG pathway. These findings suggested that PKA is possibly involved in the avoidance of excessive activation of the HOG pathway under impaired biosynthesis of complex sphingolipids.

Loss of tolerance to multiple environmental stresses due to limitation of structural diversity of complex sphingolipids

“…Msn2/4 are activated by Hog1 and involved in the rescue effect of the HOG pathway under complex sphingolipid biosynthesis–defective conditions ( Yamaguchi et al. , 2018 ; Urita et al. , 2022 ).…”

Comprehensively dissecting the hub regulation of PkaC on high‐productivity and pellet macromorphology in citric acid producing Aspergillus niger

“…As shown in Fig. 6, these data are consistent with PKA/cAMP signalling pathway that played a hub regulatory role in hyphal development, cell wall synthesis and pellet morphology by cross‐talk with the HOG‐MAPK pathway (Gutin et al ., 2015; de Assis et al ., 2018; Urita et al ., 2021) and CWI pathway (Donlin et al ., 2014; García et al ., 2017) in other fungi.…”

Ddp1 Cooperates with Ppx1 to Counter a Stress Response Initiated by Nonvacuolar Polyphosphate

“…For example, Ura2, which is downregulated in PPK-expressing cells, is phosphorylated by PKA in vitro ( 53 ). Moreover, PKA regulates the activity of Msn2/Msn4 and Yak1 through direct phosphorylation ( 35 , 40 ), and recently, it was suggested that PKA might modulate the activation of the Hog1 pathway during impaired sphingolipid biosynthesis ( 54 ). Previous work has shown that the deletion of YAK1 or MSN2 and MSN4 under conditions of low PKA activity rescues related slow-growth phenotypes ( 55 , 56 ).…”