A walk-through MAPK structure and functionality with the 30-year-old yeast MAPK Slt2

González-Rubio, Gema; Sellers-Moya, Ángela; Martı́n, Humberto; Molina, Marı́a

doi:10.1007/s10123-021-00183-z

Cited by 17 publications

(15 citation statements)

References 123 publications

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“…Schematic representation of the ER-stress signaling network and its interaction with Slt2 and the hexosamine pathway. The CWI signaling pathway from the anchored Wsc sensors to the final MAPK Slt2 (see [3,[5][6][7][8][9][10] as representative reviews) and the metabolic steps from fructose (Fruc) or glucosamine (GlcN) to glucosamine-6-phosphate (GlcN-6P) catalyzed by Gfa1 [22] and Hxk2 [49,50], respectively, are shown. Gfa1 catalyzes the first committed and rate-limiting step of the HBP, which provides UDP-N-acetylglucosamine for, among others, glycosylation and GPI-anchoring of proteins [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Rapamycin, alkaline pH, cadmium, and genotoxic or oxidative stresses, among others, are some of the diverse stimuli described for this pathway [7]. Furthermore, Slt2 has been reported to be involved in the regulation of different targets and cellular responses [10], i.e., mitophagy and pexophagy [11] or endoplasmic reticulum (ER) inheritance [12]. All of this evidences the role of the CWI pathway and Slt2 as central players in the protective response of S. cerevisiae to stress.…”

Section: Introductionmentioning

confidence: 99%

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

Sánchez-Adriá

Sanmartín

Prieto

et al. 2022

JoF

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sánchez-Adriá

Sanmartín

Prieto

et al. 2022

JoF

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“…It is well-known that the Mitogen-Activated Protein Kinase (MAPK) slt2/Mpk1 pathway and Yps1p are required for cell survival under heat stress, osmotic stress, or genotoxic stress (Truman et al, 2007;Bermejo et al, 2008;Soriano-Carot et al, 2012;Gonzalez-Rubio et al, 2021). On the one hand, Slt2/Mpk1 pathway was mutually regulated with the YPS1 gene, with Slt2 regulating YPS1 gene expression and YPS1 gene disruption capable of elevating phosphorylation of Slt2 (Krysan et al, 2005;Gagnon-Arsenault et al, 2006;Miyazaki et al, 2011;Bairwa et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of HSA-pFSHβ production by disrupting YPS1 and supplementing N-acetyl-L-cysteine in Pichia pastoris

et al. 2022

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IntroductionPichia pastoris is widely used for the production of recombinant proteins, but the low production efficiency hinders its wide application in biopharmaceuticals. Moreover, many biopharmaceutical-like proteins are accompanied by degradation during secretory expression in P. pastoris.ObjectiveIn this study, we used human serum albumin and porcine follicle-stimulating hormone β (HSA-pFSHβ) fusion protein as a model protein to investigate whether YPS1 and YPT7 gene disruption and N-acetyl-L-cysteine (NAC) supplementation have synergistic effects to inhibit the degradation of recombinant proteins.Results and discussionOur results showed that YPS1 gene disruption reduced the degradation of intact HSA-pFSHβ and increased the yield of intact protein in the culture medium and cells without affecting the integrity of the cell wall. Moreover, the beneficial effects of YPS1 gene disruption were associated with the upregulation of the MAPK signaling pathway and maintenance of redox homeostasis. YPS1 gene disruption and NAC supplementation had synergistic effects on HSA-pFSHβ production. In addition, disruption of vacuolar morphology by YPT7 gene disruption or NH4Cl treatment affected the production of recombinant HSA-pFSHβ protein. Furthermore, YPT7 gene disruption inhibited the processing of signal peptide in high-level produced HSA-pFSHβ strain. In conclusion, our results demonstrated that YPS1 disruption could reduce the degradation of intact HSA-pFSHβ proteins, and synergistically increase the yield of intact HSA-pFSHβ with NAC supplementation. This study provided a valuable reference for reducing recombinant protein degradation and therefore improving the yield of recombinant proteins in P. pastoris.

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“…In cryo-EM structures of TORC2, density attributable to the N-terminal ANK domain of Avo2 is nestled between the N-HEAT repeats 18–21 and the FAT domain in Tor2, placing Avo2 in a position to serve some regulatory role on the catalytic subunit. Indeed, we found [ 51 ] that Avo2 is a primary target of the stress-activated MAPK Slt2/Mpk1 (mammalian ortholog ERK5/MAPK7), the primary effector of the so-called yeast cell wall integrity pathway [ 74 , 75 ]. Avo2 contains nine -SP- and -TP- sites, eight residing in its C-terminal unstructured region of which five have been detected in global analyses of the S. cerevisiae phosphoproteome [ 76–80 ].…”

Section: Ancillary Torc2 Componentsmentioning

confidence: 99%

TOR complex 2 is a master regulator of plasma membrane homeostasis

Thorner

2022

Biochemical Journal

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As first demonstrated in budding yeast (Saccharomyces cerevisiae), all eukaryotic cells contain two, distinct multi-component protein kinase complexes that each harbor the TOR (Target Of Rapamycin) polypeptide as the catalytic subunit. These ensembles, dubbed TORC1 and TORC2, function as universal, centrally important sensors, integrators, and controllers of eukaryotic cell growth and homeostasis. TORC1, activated on the cytosolic surface of the lysosome (or, in yeast, on the cytosolic surface of the vacuole), has emerged as a primary nutrient sensor that promotes cellular biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane, plays a major role in maintaining the proper levels and bilayer distribution of all plasma membrane components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins). This article surveys what we have learned about signaling via the TORC2 complex, largely through studies conducted in S. cerevisiae. In this yeast, conditions that challenge plasma membrane integrity can, depending on the nature of the stress, stimulate or inhibit TORC2, resulting in, respectively, up-regulation or down-regulation of the phosphorylation and thus the activity of its essential downstream effector the AGC family protein kinase Ypk1. Through the ensuing effect on the efficiency with which Ypk1 phosphorylates multiple substrates that control diverse processes, membrane homeostasis is maintained. Thus, the major focus here is on TORC2, Ypk1, and the multifarious targets of Ypk1 and how the functions of these substrates are regulated by their Ypk1-mediated phosphorylation, with emphasis on recent advances in our understanding of these processes.

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A walk-through MAPK structure and functionality with the 30-year-old yeast MAPK Slt2

Cited by 17 publications

References 123 publications

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

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

Enhancement of HSA-pFSHβ production by disrupting YPS1 and supplementing N-acetyl-L-cysteine in Pichia pastoris

TOR complex 2 is a master regulator of plasma membrane homeostasis

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