Sec24 phosphorylation regulates autophagosome abundance during nutrient deprivation

Abstract

Endoplasmic Reticulum (ER)-derived COPII coated vesicles constitutively transport secretory cargo to the Golgi. However, during starvation-induced stress, COPII vesicles have been implicated as a membrane source for autophagosomes, distinct organelles that engulf cellular components for degradation by macroautophagy (hereafter called autophagy). How cells regulate core trafficking machinery to fulfill dramatically different cellular roles in response to environmental cues is unknown. Here we show that phosphorylation of conserved amino acids on the membrane-distal surface of the Saccharomyces cerevisiae COPII cargo adaptor, Sec24, reprograms COPII vesicles for autophagy. We also show casein kinase 1 (Hrr25) is a key kinase that phosphorylates this regulatory surface. During autophagy, Sec24 phosphorylation regulates autophagosome number and its interaction with the C-terminus of Atg9, a component of the autophagy machinery required for autophagosome initiation. We propose that the acute need to produce autophagosomes during starvation drives the interaction of Sec24 with Atg9 to increase autophagosome abundance.DOI: http://dx.doi.org/10.7554/eLife.21167.001

Crosstalk between the Secretory and Autophagy Pathways Regulates Autophagosome Formation

“…In line with previous findings showing that the COPII coat plays an active role in targeting the vesicle to its final intracellular destination (Cai et al, 2007; Lord et al, 2011), yeast Sec24 was recently shown to have a central role in engaging the vesicle with the Atg machinery during nutrient deprivation (Davis et al, 2016). In particular, phosphorylation of a cluster of amino acids on the membrane distal surface of Sec24 was found to commit COPII vesicles to autophagy.…”

“…Mutating these phosphorylation sites to alanine specifically inhibited autophagy, but not ER-Golgi transport. Failure to phosphorylate the Sec24 membrane distal surface disrupted the interaction of Sec24 with Atg9, which was shown to be needed for autophagy (Davis et al, 2016). Casein kinase 1, Hrr25, is a key kinase that phosphorylates this Sec24 surface, and both Sec24 phosphorylation and Hrr25 modulate autophagosome abundance during starvation.…”

“…Casein kinase 1, Hrr25, is a key kinase that phosphorylates this Sec24 surface, and both Sec24 phosphorylation and Hrr25 modulate autophagosome abundance during starvation. These phosphorylation events were found to be independent of the assembly of the Atg hierarchy, indicating that Sec24 phosphorylation does not indirectly disrupt autophagy by blocking the delivery of the Atg machinery to sites of autophagosome formation (Davis et al, 2016). These findings show that phosphorylation regulates the membrane rearrangements that take place during starvation induced autophagy and the COPII coat is a target of this regulation.…”

Toolbox: Creating a systematic database of secretory pathway proteins uncovers new cargo for COPI

“…Atg9 is conserved from yeast to humans and its mammalian homolog, mAtg9, localizes to the trans‐Golgi network and to late endosomes . The localization to COPI‐positive structures raises the interesting possibility that Atg9 cycles between the endosomal system and the Golgi thereby connecting different compartments recently implicated in autophagosome formation . It has also recently been published that a fraction of COPI binds polyubiquitinated cargo in endosomes for delivery to late‐Golgi .…”

Remodeling of ER ‐exit sites initiates a membrane supply pathway for autophagosome biogenesis

“…According to a recent study, phosphorylation of Sec24, the cargo receptor subunit of COPII, may be a mechanism for reprogramming the COPII vesicles toward autophagic membrane formation in yeast [63]. In place of the ERGIC, specialized COPII vesicles may bud directly from the ERES to supply the autophagic membrane.…”