Slt2 Is Required to Activate ER-Stress-Protective Mechanisms through TORC1 Inhibition and Hexosamine Pathway Activation

Abstract

Slt2, the MAPK of the cell wall integrity (CWI) pathway, connects different signaling pathways and performs different functions in the protective response of S. cerevisiae to stress. Previous work has evidenced the relation of the CWI pathway and the unfolded protein response (UPR), a transcriptional program activated upon endoplasmic reticulum (ER) stress. However, the mechanisms of crosstalk between these pathways and the targets regulated by Slt2 under ER stress remain unclear. Here, we demonstrated that ectopic expression of GFA1, the gene encoding the first enzyme in the synthesis of UDP-GlcNAc by the hexosamine biosynthetic pathway (HBP) or supplementation of the growth medium with glucosamine (GlcN), increases the tolerance of slt2 mutant cells to different ER-stress inducers. Remarkably, GlcN also alleviates the sensitivity phenotype of cells lacking IRE1 or HAC1, the main actors in controlling the UPR. The exogenous addition of GlcN reduced the abundance of glycosylated proteins and triggered autophagy. We also found that TORC1, the central stress and growth controller, is inhibited by tunicamycin exposure in cells of the wild-type strain but not in those lacking Slt2. Consistent with this, the tunicamycin-induced activation of autophagy and the increased synthesis of ATP in response to ER stress were absent by knock-out of SLT2. Altogether, our data placed Slt2 as an essential actor of the ER stress response by regulating the HBP activity and the TORC1-dependent signaling.

Constitutive activation of TORC1 signalling attenuates virulence in the cross‐kingdom fungal pathogen Fusarium oxysporum

“…Interestingly, F. oxysporum mutants in the cell wall integrity (CWI) mitogen‐activated protein kinase (MAPK) cascade also display increased sensitivity to both cell wall and high temperature stress (Segorbe et al, 2017). Although the functional link between CWI and TORC1 signalling pathways is not fully understood, a crosstalk between these two pathways has previously been suggested (Ahmed et al, 2019; Madrid et al, 2016; Sanchez‐Adria et al, 2022; Yu et al, 2014).…”

Extension of O -Linked Mannosylation in the Golgi Apparatus Is Critical for Cell Wall Integrity Signaling and Interaction with Host Cells in Cryptococcus neoformans Pathogenesis

“…TORC1 (target of rapamycin complex 1), the central stress and growth controller, is involved in activation of ribosomal biogenesis ( 56 ). A recent study in S. cerevisiae reported that the TORC1 pathway is inhibited by TM exposure in cells of the WT strain but not in those lacking Slt2 (Mpk1), indicating that Mpk1 is required to activate the ER stress-protective mechanism through TORC1 inhibition ( 57 ). It was previously reported that Mtl1 O -mannosylation mediated by both Pmt1 and Pmt2 was important for cell survival under oxidative conditions and TOR blockade in S. cerevisiae ( 58 ).…”

Constitutive activation of TORC1 signaling attenuates virulence in the cross-kingdom fungal pathogen Fusarium oxysporum

“…Interestingly, F. oxysporum mutants in the cell wall integrity (CWI) mitogen activated protein kinase (MAPK) cascade also display increased sensitivity to both cell wall and high temperature stress [55]. Although the functional link between CWI and TORC1 signaling pathways is not fully understood, a crosstalk between these two pathways has previously been suggested [21,54,56,57].…”