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New thoughts regarding Atg8 and ubiquitination

Until recently, a clear functional division between the ubiquitin-proteasome system and macroautophagy was common sense. It was thought that ubiquitination targets short-lived or damaged proteins for degradation to the proteasome, whereas macroautophagy nonselectively removes parts of the cytoplasm. The identification of receptors, which specifically recruit ubiquitinated cargoes to the autophagic machinery significantly changed this view.1,2 It became apparent that macroautophagy can selectively eliminate bulky substrates such as protein aggregates, which are resistant to unfolding and degradation by the proteasome,2,3 but also organelles and invading bacteria,4 and that ubiquitination plays an important role in these selective types of macroautophagy. On that topic, several studies have examined the role of PINK1-Parkin in mitophagy;5-13 Parkin is an E3 ubiquitin ligase that ubiquitinates various mitochondrial proteins, although it is not yet clear whether there are specific targets that are critical for initiating mitochondria degradation in mammalian cells. Of course the ubiquitin-like modifiers Atg8 and Atg12 were initially characterized in yeast,14-17 and Atg12 function was recently expanded to include its covalent attachment to the E2 enzyme Atg3 as part of the regulatory process controlling mammalian mitophagy.18 Returning to yeast, deubi-quitination is linked to ribophagy.19 This is not meant to be a complete list, because the topic of this article is not ubiquitination per se, but rather a ubiquitin-extracting protein VCP/p97 and its yeast homologue Cdc48. 
 
VCP/Cdc48 is a AAA+-ATPase chaperone-like protein that interacts with, and segregates, ubiquitinated substrates in endoplasmic reticulum-associated degradation (ERAD) and the ubiquitin-fusion domain (UFD) pathways. During Golgi complex reassembly, VCP interacts with the adaptor p47 to regulate SNARE pairing. Mutations in VCP result in inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD). Interestingly, three recent reports connect these proteins to macroautophagy. 
 
Tresse et al. and Ju et al. show that VCP is required for autophagosome maturation in mammalian cells,20,21 and Krick et al. demonstrate a related role for Cdc48 in yeast (see the punctum by Krick et al. in this issue of the journal).22 VCP mutants form enlarged, immature autophagosomes, whereas mutation of SHP1, the yeast p47 homologue, prevents completion of the autophagosome. The role of VCP/Cdc48 and p47/Shp1 in autophagy is not known; however, Shp1 interacts with Atg8, and preferentially with the lipidated form,22 and its function in autophagy appears to be independent of ubiquitin. This leads to the hypothesis that Cdc48 and Shp1 may act to extract/segregate Atg8–PE from a fusion complex to allow autophagosome formation. Whether this complex contains SNARE proteins or not is still an open question.