The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System

Abstract

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and appears to link autophagy with the UPS. Here, we review the role of ATG16 in different species. We summarize the current knowledge of its functions in autophagosome membrane expansion and autophagosome formation, in Crohn’s disease, and in bacterial sequestration. In addition, we provide information on its autophagy-independent functions and its role in the crosstalk between autophagy and the UPS.

Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling

“…ATG16L, a component of a ubiquitin-like protein conjugation system critical for elongation of the preautophagosomal membrane (Kuang et al, 2013;Xiong et al, 2018), was identified when analyses were performed to identify tumor-specific gene expression changes in human melanoma cell lines with or without silenced PTEN (Peng et al, 2016). ATG16L was up-regulated in tumors with PTEN.…”

Dictyostelium discoideum and autophagy – a perfect pair

“…In addition, autophagy-independent functions have been reported in different organisms for ATG1, ATG2, ATG3, ATG4, ATG5, ATG6, ATG12, ATG16 and PtdIns3K (Bestebroer et al, 2013, Schaaf et al, 2016, Subramani and Malhotra, 2013. This list is likely not exhaustive and also in Dictyostelium, many of the core autophagy proteins appear to fulfil autophagy-independent functions in addition to their role in canonical autophagy (Xiong et al, 2019, Xiong et al, 2015.…”

“…Although ubiquitin, ATG5, and ATG12 do not share sequence similarity, the 3D structures of the ubiquitin-like domains are highly similar, especially with respect to the a-helices and b-strands (Fischer et al, 2019, Geng and Klionsky, 2008, Tsukada and Ohsumi, 1993. D. discoideum ATG16 is composed of three distinct regions, as is the case for the ATG16 orthologs in higher eukaryotes: the N-terminal domain which is responsible for binding to ATG5, followed by a coiled-coil domain (CCD) which mediates homo-dimerisation and seven WD40 repeats in the C-terminal half of the protein, which are predicted to form a b-propeller structure (Xiong et al, 2019). This structure serves as a hub for protein-protein interactions, which appear to be crucial for autophagy-dependent or -independent functions of ATG16 (Xiong et al, 2019).…”

“…D. discoideum ATG16 is composed of three distinct regions, as is the case for the ATG16 orthologs in higher eukaryotes: the N-terminal domain which is responsible for binding to ATG5, followed by a coiled-coil domain (CCD) which mediates homo-dimerisation and seven WD40 repeats in the C-terminal half of the protein, which are predicted to form a b-propeller structure (Xiong et al, 2019). This structure serves as a hub for protein-protein interactions, which appear to be crucial for autophagy-dependent or -independent functions of ATG16 (Xiong et al, 2019). The C-terminal domain is missing in yeast ATG16 and recently, the crystal structure of the yeast ATG12~5/16 complex has been solved, showing that ATG12 and ATG16 are located on opposite sides of ATG5 and that there is no molecular interaction between ATG16 and ATG12 (Suzuki et al, 2017).…”

“…Expression of ATG16 lacking the WD40 repeat domain led to morphological changes in the intestine that resembled inflammatory bowel disease (Nagy et al, 2017). Furthermore, the C-terminal WD40 domain is important in xenophagy (Xiong et al, 2019). During infection of intestinal epithelial cells with Salmonella typhimurium, damage of the en- Fig.…”