Casein kinase 2 is essential for mitophagy

Abstract

Mitophagy is a process that selectively degrades mitochondria. When mitophagy is induced in yeast, the mitochondrial outer membrane protein Atg32 is phosphorylated, interacts with the adaptor protein Atg11 and is recruited into the vacuole with mitochondria. We screened kinase-deleted yeast strains and found that CK2 is essential for Atg32 phosphorylation, Atg32-Atg11 interaction and mitophagy. Inhibition of CK2 specifically blocks mitophagy, but not macroautophagy, pexophagy or the Cvt pathway. In vitro, CK2 phosphorylates Atg32 at serine 114 and serine 119. We conclude that CK2 regulates mitophagy by directly phosphorylating Atg32.

Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways

“…Unlike MAPK1, there are no previous studies suggesting a relationship between MAPK14 and mitophagy. Because a requirement of the MAPK14 yeast homolog Hog1 for mitophagy in yeast has been well established, [40][41][42] our finding that MAPK14 is required for mitophagy is unsurprising. However, the aspect of how MAPK1 and MAPK14 work in mitophagy is unclear, and further studies are required to determine this issue.…”

“…In particular, the molecular mechanisms of mitophagy in yeast have been well described, including identification of the mitophagy-specific protein Atg32 and the requirement of 2 MAPKs, Slt2 and Hog1, for mitophagy. [40][41][42]50,51 Because mitophagy is evolutionarily conserved from yeast to human, it is reasonable to speculate that there are similar molecular processes in mammals. Actually, we showed that 2 MAPKs, MAPK1 and MAPK14, and their upstream signaling pathways are required for starvation-or hypoxia-induced mitophagy (Figs.…”

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

“…It can be considered as an archetype of mitochondrial mitophagy receptors consisting of a transmembrane domain (TMD), anchoring it to the MOM, and an Atg8-interacting motif (AIM), also termed LIR motif, facilitating the interaction with downstream autophagy factors. Although there are additional posttranslational modifications of Atg32 known (Levchenko et al, 2016), it shares the prototypical way of receptor activation by phosphorylation of serine residues (S114 and S119) with its mammalian counterparts (Aoki et al, 2011;Kanki et al, 2013). A general model for receptor activation and the mammalian proteins that are known to be regulated by this are shown in Figure 2.…”

Peroxisomal Pex3 Activates Selective Autophagy of Peroxisomes via Interaction with the Pexophagy Receptor Atg30

“…Receptors have been described in yeast for the cytoplasm-to-vacuole targeting pathway (Atg19 and Atg34) and the selective autophagy of mitochondria (mitophagy; Atg32) and peroxisomes (pexophagy; Pichia pastoris Atg30 and Saccharomyces cerevisiae Atg36) (7)(8)(9)(10)(11). The organelle-selective autophagy receptors localize to their respective cargo surfaces and, upon phosphorylation by kinases (casein kinase 2 for Atg32 (12), Hrr25 for Atg19 (13,14) and Atg36 (14), and an unknown kinase for Atg30), are then able to interact with the scaffold protein Atg11 and a ubiquitin-like component of the PAS and phagophore (Atg8) in a random-sequential manner (15). In addition, Atg30 interacts with other autophagy proteins at the receptor protein complex (RPC), such as the scaffold protein Atg17 and the acyl-CoA-binding protein Atg37, as well as two peroxisomal membrane proteins (PMPs), Pex3 and Pex14 (16,17).…”