Pexophagy sensing and signaling in the methylotrophic yeasts

Abstract

Methylotrophic yeasts are unique eukaryotic organisms capable of utilizing the one-carbon toxic substrate, methanol. During methylotrophic growth, peroxisomes occupy 30-80 % of the cellular volume. A shift of methanol-grown cells to media with the alternative carbon sources, glucose or ethanol, induces massive peroxisome degradation. In Pichia pastoris, two morphologically distinct events have been observed namely, macro- and microautophagy. In other species, macroautophagy was mostly noted under massive peroxisome degradation. It was found that genes involved in non-specific autophagy (most of them known as ATG genes) also participate in carbon source-induced pexophagy. Many ATG genes have been discovered using methylotrophic yeasts models, mainly in P. pastoris, due to convenient and easy methods to monitor pexophagy. However, the mechanisms of glucose and ethanol sensing and signaling, which initiate the subsequent events of micro- and macroautophagy are poorly understood. Similarly, the nature of the low-molecular-weight effectors, derivatives of glucose and ethanol, which induce pexophagy, has not been identified. P. pastoris possesses a single glucose sensor, Gss1p, ortholog of the S. cerevisiae high- and low-affinity glucose sensors Snf3p and Rgt2p, respectively. The Gss1 protein participates in glucose sensing and is involved in pexophagy and glucose catabolite repression. In the yeast P. pastoris, the orthologs of GPCR signaling proteins, Gpr1p and Gpa2p, do not participate in pexophagy upon glucose signaling. In this yeast species, the α-subunit of phosphofructokinase Pfk1p and the mitogen-activated protein kinase (MAPK) Slt2p are involved in glucose signaling of pexophagy. Ethanol signaling studied in P. methanolica mutants defective in ethanol catabolism suggested that glyoxylic acid is the most probable substance, which triggers pexophagy.