RTG-dependent mitochondria-to-nucleus signaling is regulated by MKS1 and is linked to formation of yeast prion [URE3]

An important function of the RTG signaling pathway is maintenance of intracellular glutamate supplies in yeast cells with dysfunctional mitochondria. Herein, we report that MKS1 is a negative regulator of the RTG pathway, acting between Rtg2p, a proximal sensor of mitochondrial function, and the bHLH transcription factors Rtg1p and Rtg3p. In mks1Delta cells, RTG target gene expression is constitutive, bypassing the requirement for Rtg2p, and is no longer repressible by glutamate. We show further that Mks1p is a phosphoprotein whose phosphorylation pattern parallels that of Rtg3p in response to activation of the RTG pathway, and that Mks1p is in a complex with Rtg2p. MKS1 was previously implicated in the formation of [URE3], an inactive prion form of a negative regulator of the nitrogen catabolite repression pathway, Ure2p. rtgDelta mutations induce [URE3] and can do so independently of MKS1. We find that glutamate suppresses [URE3] formation, suggesting that the Mks1p effect on the formation of [URE3] can occur indirectly via regulation of the RTG pathway.