Metabolic Respiration Induces AMPK- and Ire1p-Dependent Activation of the p38-Type HOG MAPK Pathway

Adhikari, Hema; Cullen, Paul J.

doi:10.1371/journal.pgen.1004734

Cited by 45 publications

(60 citation statements)

References 160 publications

(189 reference statements)

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“…Therefore, the UPR does not play a major role in regulating the mating pathway. Activation of the HOG pathway does occur in response to galactose, which also requires Ire1p (58). The results shown here bring to light a new role for the UPR in regulating fungal behavioral responses through the regulation of a differentiation (ERK-type) MAPK pathway.…”

Section: Underglycosylatedmentioning

confidence: 59%

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Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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bSignaling mucins are evolutionarily conserved regulators of signal transduction pathways. The signaling mucin Msb2p regulates the Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. The cleavage and release of the glycosylated inhibitory domain of Msb2p is required for MAPK activation. We show here that proteolytic processing of Msb2p was induced by underglycosylation of its extracellular domain. Cleavage of underglycosylated Msb2p required the unfolded protein response (UPR), a quality control (QC) pathway that operates in the endoplasmic reticulum (ER). The UPR regulator Ire1p, which detects misfolded/underglycosylated proteins in the ER, controlled Msb2p cleavage by regulating transcriptional induction of Yps1p, the major protease that processes Msb2p. Accordingly, the UPR was required for differentiation to the filamentous cell type. Cleavage of Msb2p occurred in conditional trafficking mutants that trap secretory cargo in the endomembrane system. Processed Msb2p was delivered to the plasma membrane, and its turnover by the ubiquitin ligase Rsp5p and ESCRT attenuated the filamentous-growth pathway. We speculate that the QC pathways broadly regulate signaling glycoproteins and their cognate pathways by recognizing altered glycosylation patterns that can occur in response to extrinsic cues. Signaling mucins are evolutionarily conserved regulators of signal transduction pathways (1-4). Signaling mucins are composed of a highly glycosylated extracellular domain that contains a mucin homology domain (MHD), which is defined by tandem repeats rich in Ser/Thr/Pro residues. The extracellular domain is connected by a single-pass transmembrane (TM) alpha helix to a cytosolic signaling domain, which associates with a diverse array of proteins that regulate mitogen-activated protein kinase (MAPK) pathways, Akt, ␤-catenin, and other pathways (5-8). Signaling mucins are overexpressed in different cancers, where they contribute to cell proliferation and metastasis (6). They are diagnostic biomarkers for cancers (9) and targets for immunotherapies (10,11). Therefore, the mechanisms by which signaling mucins and related glycoproteins are regulated is of intense interest.In the budding yeast Saccharomyces cerevisiae, the mucin-like glycoprotein Msb2p regulates the MAPK pathway that controls filamentous growth, a cell differentiation behavior that occurs in response to nutrient limitation (12-14). The extracellular domain of Msb2p is extensively glycosylated. Msb2p is modified by Nlinked and O-linked glycosylation and contains a canonical MHD that is itself highly glycosylated (15, 16). In a landmark study, Yang et al. identified Pmt4p as the major O-mannosyltransferase for Msb2p (17). Pmt4p is a member of an evolutionarily conserved protein mannosyl transferase (Pmt) gene family (2, 18). Msb2p also contains a cytosolic signaling domain. The cytosolic domain of Msb2p associates with the Rho GTPase Cdc42p (15), which is a ubiquitous regulator of cell polarity and signaling...

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Section: Underglycosylatedmentioning

confidence: 59%

“…Growth in galactose modestly induced the UPRE-lacZ reporter (Fig. 3A) (58). Induction of the UPR by galactose required Ire1p (Fig.…”

Section: Underglycosylatedmentioning

confidence: 90%

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Vadaie

Chow

et al. 2015

Molecular and Cellular Biology

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“…The mechanistic basis for the antagonistic roles of these PI(4)P kinases is not clear and underscores the importance of future studies of PI(4)P in regulation of the p38 MAPK pathway. The filamentous-growth (ERK-type) and HOG (p38-type) MAPK pathways have opposing functions in the cell (7,106,(153)(154)(155). The fact that PI(4)P has different effects on ERK and p38 MAPK pathways could, in principle, influence the specificity of MAPK outputs.…”

Section: Discussionmentioning

confidence: 99%

“…Each MAPK pathway in yeast responds to a different stimulus. Under some circumstances, several MAPK pathways are required to mount an appropriate response (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Role of Phosphatidylinositol Phosphate Signaling in the Regulation of the Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Adhikari

Cullen

2015

Eukaryot Cell

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Reversible phosphorylation of the phospholipid phosphatidylinositol (PI) is a key event in the determination of organelle identity and an underlying regulatory feature in many biological processes. Here, we investigated the role of PI signaling in the regulation of the mitogen-activated protein kinase (MAPK) pathway that controls filamentous growth in yeast. Lipid kinases that generate phosphatidylinositol 4-phosphate [PI(4)P] at the Golgi (Pik1p) or PI(4,5)P2 at the plasma membrane (PM) (Mss4p and Stt4p) were required for filamentous-growth MAPK pathway signaling. Introduction of a conditional allele of PIK1 (pik1-83) into the filamentous (⌺1278b) background reduced MAPK activity and caused defects in invasive growth and biofilm/mat formation. MAPK regulatory proteins that function at the PM, including Msb2p, Sho1p, and Cdc42p, were mislocalized in the pik1-83 mutant, which may account for the signaling defects of the PI(4)P kinase mutants. Other PI kinases (Fab1p and Vps34p), and combinations of PIP (synaptojanin-type) phosphatases, also influenced the filamentous-growth MAPK pathway. Loss of these proteins caused defects in cell polarity, which may underlie the MAPK signaling defect seen in these mutants. In line with this possibility, disruption of the actin cytoskeleton by latrunculin A (LatA) dampened the filamentous-growth pathway. Various PIP signaling mutants were also defective for axial budding in haploid cells, cell wall construction, or proper regulation of the high-osmolarity glycerol response (HOG) pathway. Altogether, the study extends the roles of PI signaling to a differentiation MAPK pathway and other cellular processes.M APK (mitogen-activated protein kinase) pathways are evolutionarily conserved signal transduction modules (1, 2). MAPK cascades regulate the response to environmental challenges, such as changes in osmolarity, nutrient starvation, DNA damage, and damage to cell integrity. In the budding yeast Saccharomyces cerevisiae, MAPK pathways regulate cell wall integrity (3), pheromone response or mating (4), filamentous growth (5), and the response to high osmolarity (high-glycerol response [HOG] pathway [6]). Each MAPK pathway in yeast responds to a different stimulus. Under some circumstances, several MAPK pathways are required to mount an appropriate response (7-11).The filamentous-growth MAPK pathway regulates differentiation to the filamentous cell type (12-14) and the development of biofilms or mats (15). During filamentous growth, the MAPK pathway, together with other pathways (16-18), induces a delay in the cell cycle (19), a reorganization of cell polarity, which leads to a distal-unipolar budding pattern (12,13,20,21), and elevated expression of the cell adhesion molecule Flo11p (22). The developmental foraging responses that occur in S. cerevisiae are evolutionarily conserved across many fungal species. In pathogenic fungi, like Candida albicans, an orthologous differentiation MAPK pathway (called the Cek1p pathway) regulates filamentous/hyphal growth and biofilm formation ...

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“…In mammalian neuronal cells, the p38 MAP kinase (orthologous to os-2) has been shown to regulate O-linked β-N-acetylglucosamine protein modifications, particularly in response to glucose deprivation (39). In S. cerevisiae and C. albicans, the p38 MAP kinase ortholog Hog1 functions with the nutrient-sensing Kss1 MAP kinase to regulate morphological responses to the nonpreferred carbon source, galactose (40). However, unlike the N. crassa OS pathway-mediated response to starvation, the S. cerevisiae Hog1-mediated response to the nonpreferred sugar galactose activates the expression of genes required for the response to hyperosmotic shock, including genes in the glycerol-production pathway (40).…”

Section: The Os Pathway Regulates the Expression Of Genes Involved Inmentioning

confidence: 99%

Network of nutrient-sensing pathways and a conserved kinase cascade integrate osmolarity and carbon sensing in Neurospora crassa

Huberman

Coradetti

Glass

2017

Proc. Natl. Acad. Sci. U.S.A.

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Identifying nutrients available in the environment and utilizing them in the most efficient manner is a challenge common to all organisms. The model filamentous fungus Neurospora crassa is capable of utilizing a variety of carbohydrates, from simple sugars to the complex carbohydrates found in plant cell walls. The zinc binuclear cluster transcription factor CLR-1 is necessary for utilization of cellulose, a major, recalcitrant component of the plant cell wall; however, expression of clr-1 in the absence of an inducer is not sufficient to induce cellulase gene expression. We performed a screen for unidentified actors in the cellulose-response pathway and identified a gene encoding a hypothetical protein (clr-3) that is required for repression of CLR-1 activity in the absence of an inducer. Using clr-3 mutants, we implicated the hyperosmotic-response pathway in the tunable regulation of glycosyl hydrolase production in response to changes in osmolarity. The role of the hyperosmotic-response pathway in nutrient sensing may indicate that cells use osmolarity as a proxy for the presence of free sugar in their environment. These signaling pathways form a nutrient-sensing network that allows N. crassa cells to tightly regulate gene expression in response to environmental conditions. MAP kinase cascade | carbon metabolism | hyperosmotic response | carbon catabolite repression | plant biomass degradation

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Metabolic Respiration Induces AMPK- and Ire1p-Dependent Activation of the p38-Type HOG MAPK Pathway

Cited by 45 publications

References 160 publications

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Role of Phosphatidylinositol Phosphate Signaling in the Regulation of the Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

Network of nutrient-sensing pathways and a conserved kinase cascade integrate osmolarity and carbon sensing in Neurospora crassa

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