Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways.

The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.

Selective autophagy of damaged mitochondria requires autophagy receptors optineurin (OPTN), NDP52 (CALCOCO2), TAX1BP1, and p62 (SQSTM1) linking ubiquitinated cargo to autophagic membranes. By using quantitative proteomics, we show that Tank-binding kinase 1 (TBK1) phosphorylates all four receptors on several autophagyrelevant sites, including the ubiquitin-and LC3-binding domains of OPTN and p62/SQSTM1 as well as the SKICH domains of NDP52 and TAX1BP1. Constitutive interaction of TBK1 with OPTN and the ability of OPTN to bind to ubiquitin chains are essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 in turn phosphorylates OPTN's UBAN domain at S473, thereby expanding the binding capacity of OPTN to diverse Ub chains. In combination with phosphorylation of S177 and S513, this posttranslational modification promotes recruitment and retention of OPTN/TBK1 on ubiquitinated, damaged mitochondria. Moreover, phosphorylation of OPTN on S473 enables binding to pS65 Ub chains and is also implicated in PINK1-driven and Parkin-independent mitophagy. Thus, TBK1-mediated phosphorylation of autophagy receptors creates a signal amplification loop operating in selective autophagy of damaged mitochondria.A s a cell survival pathway, autophagy selectively frees the cytosolic compartment from bulky protein aggregates, invading bacteria or damaged organelles such as mitochondria and peroxisomes (1, 2). In this context, the posttranslational modifier ubiquitin (Ub) has been widely recognized as a selective signal driving autophagy of such cellular components and cargoes (3, 4). Recently, ubiquitin itself has been discovered to be phosphorylated to promote autophagic clearance of damaged mitochondria (mitophagy; reviewed in refs. 5 and 6). Ser/Thr kinase PINK1 phosphorylates S65 of Ub, which is critical for two steps of this process: allosteric activation of the E3 Ub ligase Parkin and recruitment of the autophagic machinery, including autophagy receptors (7)(8)(9)(10)(11)(12)(13)(14).Autophagy receptors function as decoders for the various ubiquitin signals on cargoes, linking cargoes to autophagosomal membranes (4); however, the basis of their individual recruitment to cargo as well as their distinct and cooperative functions in cargo sequestration are still poorly understood. The autophagy receptors optineurin (OPTN) and p62 are first activated by protein kinases to effectively target autophagic membranes or their polyUb cargo (15-17). TANK-binding kinase 1 (TBK1) phosphorylates OPTN on S177, thereby enhancing LC3-binding affinity and autophagic clearance of cytosolic Salmonella (15). Activity and specificity of TBK1 are defined by adaptor proteins; these recruit TBK1 to microdomains on ubiquitinated Salmonella or mitochondria, thereby facilitating its local clustering and activation (18), where it in turn can phosphorylate autophagy receptors (15). It is relevant to stress that a number of mutations in both OPTN and TBK1 have been identified in patients suffering from amyotrophic lateral sclerosis (ALS) and...

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

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