Structure biology of selective autophagy receptors

Abstract

Autophagy is a process tightly regulated by various autophagy-related proteins. It is generally classified into non-selective and selective autophagy. Whereas non-selective autophagy is triggered when the cell is under starvation, selective autophagy is involved in eliminating dysfunctional organelles, misfolded and/or ubiquitylated proteins, and intracellular pathogens. These components are recognized by autophagy receptors and delivered to phagophores. Several selective autophagy receptors have been identified and characterized. They usually have some common domains, such as motif, a specific cargo interacting (ubiquitin-dependent or ubiquitin-independent) domain. Recently, structural data of these autophagy receptors has been described, which provides an insight of their function in the selective autophagic process. In this review, we summarize the most up-to-date findings about the structure-function of autophagy receptors that regulates selective autophagy. [BMB Reports 2016; 49(2): 73-80]

The 1:2 complex between RavZ and LC3 reveals a mechanism for deconjugation of LC3 on the phagophore membrane

“…It is tempting to speculate that cleaved LC3 still possesses binding affinity to LIR motifs, which are present in numerous autophagic molecules including autophagy receptors and the autophagy core machinery. 8,10,14,40 Therefore, the RavZ-generated product has a significant effect not only on the function of ATG4B, but also on the entire autophagy system in the host. In an evolutionary context, L. pneumophila has evolved this superior mechanism, which effects survival in host cells.…”

“…3,4 Selective autophagy requires specific autophagy receptors for specific types of cargo, in that receptor molecules are present for target recognition and removal of various cellular structures, including protein aggregates, various cellular organelles, and intracellular pathogens. [5][6][7][8] In order to maintain the selectivity of the process, autophagic receptors that simultaneously bind target substrates and the key autophagic molecule Atg8 (LC3 in mammals) are required. 3 In addition to its role in the proteasomal degradation system, ubiquitination has been found to play a key role in autophagy by marking specific targets for autophagy-mediated degradation.…”

“…9 To date, 5 ubiquitin (Ub)-binding autophagic receptors, NBR1, SQSTM1/p62, OPTN (optineurin), CALCOCO2/NDP52 and TOLLIP, are known to interact with LC3 through the so-called LC3-interacting region (LIR) motif. 8,[10][11][12][13][14][15] Although a basal level of autophagy occurs in most cells, autophagy activity can increase when specific events occur, such as bacterial infection. 16,17 When bacteria invade cells, hosts implement autophagy, in combination with an immune response, to remove the pathogen.…”

Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease

“…Finally, the IBD risk gene SLC39A8 encodes a solute carrier that transports manganese and zinc into cells as an electroneutral metal/bicarbonate symporter 118 . The antibacterial autophagy adapter proteins NDP52, p62, optineurin, and NBR1 each contain a zinc finger motif that requires coordination of a zinc ion, and this domain in NDP52 is required for ubiquitin binding and recognition 69, 119, 120 . It is tempting to speculate that impaired zinc transport associated with polymorphisms in SLC39A8 might alter antibacterial autophagy with direct consequences on microbial composition 121, 122 .…”

Autophagy in Peripheral Neuropathy

“…Autophagy receptors are proteins that bind to both LC3-II and the ubiquitinated proteins to be degraded, and ensure that the damaged proteins are localized inside the autophagosome. Many autophagy receptors have been identified, among them are SQSTM1/p62, NBR1, OPTN, NIX [71][72][73]. Autophagy can be divided into two types depending on the protein cargo to be degraded; bulk autophagy and selective autophagy.…”