Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Abstract

Background: Inhibition of complex sphingolipid synthesis by inositol starvation activates the PKC-MAPK signaling pathway. Results: Sir2p-dependent telomeric silencing is activated by interrupting sphingolipid synthesis and requires the MAPK, Slt2p. Conclusion: Telomeric silencing is regulated by PKC-MAPK signaling in response to interruption of sphingolipid synthesis. Significance: Sphingolipid metabolism plays an important role in regulating silencing and chronological life span.

Characterization of the S. cerevisiae inp51 mutant links phosphatidylinositol 4,5-bisphosphate levels with lipid content, membrane fluidity and cold growth

“…Thus, membrane stress induced by increased ambient temperature appears to modulate the turnover of lipid messengers that, in turn, regulate the activation of effectors involved in lipid homeostasis. Consistent with this, inhibiting inositol-containing sphingolipid metabolism, either by inositol starvation or treatment with agents that block sphingolipid synthesis, also triggers the CWI pathway signaling [53] in a way that depends on the pool of PI(4)P and PI(4,5)P 2 [47] (Fig. 1).…”

The capacity of Aspergillus niger to sense and respond to cell wall stress requires at least three transcription factors: RlmA, MsnA and CrzA

“…AbaA-induced block of sphingolipid synthesis in S. cerevisiae has multiple consequences: the transport of proteins from the ER to the plasma membrane is inhibited, the functionality of nutrient transporters at the plasma membrane as well as plasma membrane integrity is compromised, and actin assembly as well as chitin deposition are disturbed [ 22 ],[ 23 ]. AbaA therefore activates the MAP kinase Slt2p of the CWI pathway and the TORC2-Slm1/2p-Ypk1p-Orm1/2p cascade as compensatory responses in S. cerevisiae [ 24 ]-[ 26 ]. The transcriptome data suggest that similar processes were affected in A. niger germlings when stressed with AbaA: proteins predicted to function in (i) lipid biosynthesis, (ii) vesicle transport from the ER to the Golgi, (iii) chitin, α-1,3-glucan and β-1,3-glucan synthesis and remodeling, (iv) actin polarization and (v) nutrient transport were significantly up-regulated in AbaA-treated A. niger cells (Figure 1 A and B and Additional file 3 ).…”

The response to inositol: Regulation of glycerolipid metabolism and stress response signaling in yeast

“…However, many of the genes identified as being activated in genome wide microarray studies of wild type cells growing in the absence of inositol are not involved in lipid metabolism and are not regulated in coordination with INO1 and coregulated genes of lipid metabolism. Rather, they are targets of stress response pathways that are activated when wild type cells are grown in the absence of inositol (Henry et al, 2012; Jesch et al, 2010; Jesch et al, 2006; Jesch et al, 2005; Lee et al, 2013; Nunez et al, 2008); a topic discussed below.…”

“…The activation the PKC-MAPK signaling pathway during inositol starvation leads to the up-regulation of genes involved in cell wall organization and biogenesis controlled by the Rlm1p transcription factor (Nunez et al, 2008), which may relieve plasma membrane stress when inositol sphingolipid synthesis is reduced. In addition, the triggering of PKC-MAPK signaling by inositol starvation, or by interrupting inositol sphingolipid synthesis, results in increased Sir2p-dependent telomeric silencing (Lee et al, 2013), presumably through phosphorylation of Sir3p, a known target of Slt2p (Ai et al, 2002; Ray et al, 2003) and component of the highly conserved Sir complex (Hecht et al, 1996; Strahl-Bolsinger et al, 1997). Thus, inositol sphingolipid metabolism controls multiple downstream stress responses.…”