Autophagy (macroautophagy) is a lysosome-dependent catabolic pathway that degrades damaged organelles, protein aggregates, microorganisms, and other cytoplasmic components. Autophagy was previously considered to be nonselective; however, studies have increasingly established that autophagy-mediated degradation is highly regulated. Selective autophagy regulates plenty of specific cellular components through specialized molecules termed autophagy receptors, which include p62, NBR1, NDP52, optineurin, and VCP among others. Autophagy receptors recognize ubiquitinated cargo and interact with the LC3/GABARAP/Gate16 protein on the membrane of nascent phagophore. In this review, we summarize the advances in the molecular mechanisms of selective autophagy adaptor proteins.
- selective autophagy
- adaptor proteins
The various functions of eukaryotic organisms depend largely on the existence of highly efficient regulation mechanisms. Each physiologic activity involves the production of several molecules whose half-life must be controlled by degradation system to maintain homeostasis. Up to the present time, two systems of degradation molecules or organelles are known: (a) ubiquitin-proteasome system (UPS) and (b) autophagy, a lysosome-dependent degradation system. The precise mechanisms to lead the substrate to UPS or autophagy are not understood completely. However, it is known that ubiquitin is a key protein to regulate the substrate recognition through the conjugation of a single ubiquitin monomer (monoubiquitination) or sequential conjugation of several ubiquitin moieties (polyubiquitination). The conjugation of four ubiquitin monomers is sufficient signal to allow the ubiquitylated target protein to be recognized by UPS . The specificity in the UPS is generated by the ability of ubiquitin to form eight different chain linkages on itself, through its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63). K48 ubiquitin chain is the most well studied and was originally identified as the signal to target proteins to proteasomal degradation . K11 and K63 ubiquitin chains are more related to signal for nonproteolytic functions as DNA repair and cell signaling, but a recent study shows that heterotypic K11/K48-polyUb chains bind to the proteasome and facilitate the degradation of cyclin B1 . Whereas UPS is the major degradation pathway for short-lived and regulatory proteins, autophagy is more linked with the elimination of long-lived proteins and organelles. The selectivity of autophagy degradation is conferred by K63 ubiquitin chains [4, 5] (Figure 1). Autophagy was first described as a nonselective bulk degradation system, and now the accumulated evidence indicates that autophagy can be highly selective. Nonselective autophagy is triggered as a response to starvation and implies the random formation of the autophagosomes with the subsequent capture of any organelle or molecule near the autophagosome. In contrast, the selective autophagy is involved in the recruitment of different adaptor proteins that interact with Atg proteins and target organelles or molecules to be degraded [6, 7]. It is possible to distinguish various types of selective autophagy, depending on the cargo that is captured and degraded: lipid droplets (lipophagy), mitochondria (mitophagy), ER (reticulophagy), pathogens (xenophagy), and aggregation-prone proteins (aggrephagy) , among others. Nevertheless, the precise mechanism of cargo recognition remains unclear; the molecular characterization of autophagy receptors, initially SQSTM1/p62 and NBR1, has revealed that ubiquitination is involved in substrate selectivity. Most autophagy receptors have a ubiquitin-binding domain (UBD) and LC3-interacting region (LIR). The UBD domains attach to target molecules or organelles, and LIR domain interacts with LC3/GABARAP/Gate16 protein in autophagy to facilitate autophagosome formation, transport, and/or maturation . The core of LIR consists of D/E, D/E, D/E, F/W/Y, X, X, L/I/V, and D; the phosphorylation of this domain enhances the affinity with LC3/GABARAP/Gate16 protein . In this chapter, we discuss the recent knowledge on autophagy receptors and their role in selective autophagy.
SQSTM1/p62 (referred to hereafter as p62) was initially identified as a phosphotyrosine-independent binding of a 62 kDa (gave p62 its name) to the Src homology 2 (SH2) domain . Subsequently, the term sequestosome-1 (SQSTM1) was assigned for its capacity to sequester polyubiquitinated protein to cytoplasmic storage before its degradation by the proteasome, protecting the cytosol from the toxic effect of misfolded proteins . Currently, p62 has been considered a protein with pleiotropic activities, derived from their multiple domains, which interact with several molecules involved in the cellular death, oxidative stress, inflammatory response, and recognition of molecules to be degraded by UPS or autophagy [10, 11]. Recent studies have reported that mTOR activation depends on p62 as a key regulator of the nutrient-sensing pathway .
p62 is a multifunctional protein of 440-amino acids that is conserved in metazoans but not in plants and fungi . Refractory to Sigma P (Ref(2)P) is a homologue protein of mammalian p62 in Drosophila melanogaster, that regulates protein aggregation in adult brain . p62 has six functional domains: the N-terminal Phox/Bem1 domain (PB1, 21–103 aa), a ZZ-type zing finger domain (ZnF, 128–163 aa), TRAF6-binding domain (TB, 225–250 aa), a short LC3-interacting region (LIR, 321–345 aa), KEAP1-interacting region motifs (KIR, 346–359), and ubiquitin-associated domain (UBA, 386–440 aa) which is localized in C-terminal end (Figure 2) .
PB1 domains, ZZ zinc finger, KIR, and UBA can bind several proteins to participate in inflammatory responses and receptor-mediated signal transduction. PB1 has been associated with atypical protein kinase C (aPKC) to activate NF-kB signaling pathway. The ZZ zinc finger domain is responsible for binding the receptor interacting protein (RIP) to regulate the inflammatory response. The KIR region of this scaffold protein is a regulator for Nrf2, and its activation induces transcription of oxidative stress response genes [11, 15].
p62 provides a link between the degradation of ubiquitin cargo by UPS or autophagy through the UBA domain. The PB1, LIR, and UBA domains are implied in the degradation of ubiquitinated cargo by selective autophagy. UBA domain is responsible for noncovalent binding with polyubiquitinated cargos, through serine 403 phosphorylation by casein kinase 2 (CK2), which increases the affinity for ubiquitinated chains [16, 17]. PB1 domain is involved in self- and heteroligomerization with NBR1 (another receptor of selective autophagy) [18–20], and LIR region is important to LC3 interaction. It has been hypothesized that the activity of p62, in selective autophagy, requires a sequential interaction. Initially, there must be an interaction of p62 with ubiquitin proteins, and then aggregation of complex protein oligomerization to itself or with NBR1, and these aggregates are finally degraded by autolysosomes [7, 21, 22]. This order is altered in defects of autophagy, where firstly accumulations of p62 proteins are present and later are ubiquitinated [23, 24].
Furthermore, p62 is an autophagy receptor that can bind proteins to be degraded by selective autophagy as aggregates of misfolded proteins, damaged mitochondria, peroxisomes, and intracellular bacteria, which are ubiquitinated and targeted for clearance by autophagy [7, 25]. Several works have evidenced that p62 has a critical role in the normal functioning of mitochondria. p62 is localized to mitochondria under physiological conditions and plays an important role in mitochondrial morphology, genome integrity, and mitochondrial import of transcription factors. When p62 is deleted, it leads to mitochondrial fragmentation and mitochondrial dysfunction . The role of p62 as adaptor receptor in mitophagy is currently debated. Geisler and colleagues reported that p62 with PINK1 y Parkin molecules has a key role in the sequential mitophagy process. p62 colocalized with Parkin on clustered mitochondria after the induction of mitophagy by carbonyl cyanide m‑chlorophenylhydrazone (CCCP) treatment, and the silence of p62 by siRNA resulted in a significant loss of mitochondrial clearance [27, 28]. In contrast, Narendra and colleagues mentioned that p62 is not indispensable in the mitophagy; in HeLa cells with siRNA directed against p62, no difference was found in lacking mitochondria after the induction of mitophagy but is important in clustering of depolarized mitochondria [29, 30]. Similarly, in pexophagy, the role of p62 is not clear. p62 has been involved in the clustering of peroxisomes that were labeled with ubiquitin to selective degradation , but recent work suggests that p62 is responsible for clustering, and only NBR1 is essential for peroxisome degradation by autophagy .
Adaptor p62 protein has an important role in the xenophagy, which is responsible for restriction of the replication of several intracellular microorganisms. The role of p62 has been more explored in infections by intracellular bacteria. Bacteria such as
The high relevance of p62 as a signaling hub implies their efficient regulation. When p62 is disregulated or dysfunctional, there are multiple consequences. Several studies have implicated p62 aggregates in cancer, inflammation, neurodegenerative disease, liver disease, and aging [10, 13, 20, 39].
Neighbor of BRCA1 gene 1 (NBR1) is another cargo receptor that is selectively degraded by autophagy. NBR1 was originally cloned as a candidate gene for the ovarian cancer antigen CA125 . Given the similarity and interaction with p62, NBR1 has been studied in cell signaling and differentiation . In 2009, Kirkin and colleagues have shown that NBR1 was involved in autophagic degradation of ubiquitinated targets .
NBR1 was recognized as a direct binding partner of the autophagosome-specific ATG8/LC3/GABARAP modifiers both in vitro and in vivo. NBR1 has similar domain architecture as p62 and shares several key features with p62 though differs in sequence and size. Both proteins share a very similar overall domain architecture, consisting of an N-terminal PB1(residues 5–85) domain, a ZZ-like zinc finger domain (residues 215–259), a two-domain light-chain-3-interacting regions LRS1 (residues 540–636) and LRS2 (residues 727–738, the LRS2 does not have the core consensus motif W/YXXL/I, most likely representing a novel type of LC3-interacting sequence), and a C-terminal ubiquitin-associated (UBA) domain (Figure 2) .
NBR1 binds strongly to ubiquitin via its UBA domain with a bias toward the K63-linked polyUb chains . NBR1 undergoes dimerization via the coiled-coil domain. NBR1 can directly bind to p62, and together they act as cargo receptors for autophagic degradation of polyubiquitylated aggregates and peroxisomes [43–45]. In the absence of p62, NBR1 interacts with misfolded and ubiquitinated proteins for degradation by autophagy . Moreover, it is known that NBR1 promotes cell differentiation, may act as a tumor suppressor, and is also involved in bone remodeling [46, 47]. NBR1 also is involved in protein misfolding disorders such as body myositis sporadic inclusion, and autophagic degradation may have a role in the pathology .
The nuclear dot protein 52 kD (NDP52) also named as calcium binding and coiled-coil domain 2 (CALCOCO2) is a 446-amino acid protein. Discovered in 1995, it was first erroneously found as part of the nuclear domains (ND10) called Kr bodies or PLM-containing oncogenic domains (POD), consisting of protein aggregates detected as dots (approximately 10) by autoimmune sera or monoclonal antibodies. By 1997, Sternsdorf and colleagues found by using polyclonal sera anti-NDP52 that the protein localization is restricted to the cytoplasm but not ND10 and confirmed an increase of NDP52 transcripts when cells were treated with IFN-γ .
NDP52 has a predicted molecular mass of 52 kD and exhibits an N-terminal skeletal muscle, and kidney-enriched inositol phosphatase carboxyl homology (SKICH) domain (aa 1–127), a central coil-coiled domain with zipper leucine motifs (aa 140–420) and the C-terminus presents homology with Lin11, Isl-1, and Mec-3 (LIM) domains containing two zinc finger arrangements involved in protein-protein interactions as ubiquitin (Figure 2) (aa 421–446) [50–52]. There are two paralogs existing, CoCoA (also known as Calcoco1) and Tax1BP1 (also known TXBP151). The CoCoA paralog comprises SKICH domains and LIM domains as NDP52, but it lacks an ubiquitin-binding domain. Therefore, it did not decorate bacteria when they escaped to the cytosol .
First studies linking NDP52 to a physiological process showed that after infection with
As part of the autophagosome maturation, it was found that NDP52 interacts with myosin VI via RRL motif, and such interaction recruits myosin VI to deliver endosomal membranes to the nascent autophagosome [60, 61]. This function of NDP52 is independent of its function in xenophagy and involves a different binding domain .
Recently, it has been demonstrated that NDP52 also plays a role in regulation. The Toll-like receptor (TLR) signaling serves as, an example, the selective autophagic degradation of Toll/interleukin-1 receptor homology domain-containing adaptor-inducing interferon (TRIF), and TRAF6 is mediated by this receptor. The mechanism involves the polyubiquitination of NDP52 by TRAF6 to acquire the ability to form aggregates of polyubiquitinated TRAF6 [63, 64]. The regulation of the miRNA activity is another example; recently, it has been discovered that the miRNA-processing enzyme DICER and the miRNA effector AGO2 are a target by NDP52 for their degradation via autophagy . Another target of NDP52 includes the RNA retrotransposon, and the degradation of this RNA via autophagy helps to maintain the stability of the genome . More recently, Heo and colleagues found that the PINK1-PARKIN mitochondrial ubiquitination pathway promotes mitophagy by recruiting TBK1 kinase which binds to NDP52 and other autophagy receptors to induce autophagy of mitochondria [67, 68].
Some studies with viruses have related autophagy to anti- or pro-viral roles; NDP52 has been involved in promoting viral replication of chikungunya virus (CHIKV) when interacts with the nonstructural protein nsP2 in infected human cells .
Although autophagy has a protective role against some intracellular bacteria, some studies indicate that NDP52 has a relation with Crohn’s disease, and Ellinghaus and colleagues found an association between the disease and a missense mutation in affected individuals [70, 71]. Additionally, NDP52 has been involved in Alzheimer’s disease where it has a protective role in facilitating the clearance of phosphorylated tau [72, 73].
Optineurin was first described by Li and colleagues . They were looking for proteins that interact with the early region 3 (E3) 14.7 K protein in the yeast two-hybrid system. E3 14.7 K is synthesized by E3 in group C of adenovirus and is an inhibitor of NF-kB cytolysis. They found a protein with the ability to interact with E3 14.7K and named as FIP-2 (for 14.7K interacting protein), and FIP-2 interacts with E3 14.7K in the cytoplasm and caused redistribution of the protein. Also, FIP-2 reversed the protective effect of E3 14.7K on cell death induced by TNF-α. After, Schwamborn and colleagues described that FIP-2 had a strong homology to NF-kB essential modulator (NEMO) and named as NEMO-related protein (NRP). They found that NRP was associated with Golgi apparatus and is de novo expressed by interferon and TNF-α . Rezaie and colleagues coined the name optineurin (optic neuropathy-inducing protein) after discovering that this molecule was associated with diseases such as normal tension glaucoma and a subtype of primary open-angle glaucoma .
Optineurin is a 67 KDa intracellular protein found in different tissues , and optineurin gene encodes an 884-amino acid protein and contains three noncoding exons and 13 exons that code for a 577-amino acid protein . The mRNA can be found in 3 isoforms as a result of alternative splicing . Optineurin has been described in different tissues such as spleen, kidney, skeletal muscle, brain, heart, lung, pancreas, and eyes of various species: human, mouse, and chicken [74, 78, 79]. The UPS is a very important pathway to recycle optineurin, but in situations where optineurin is upregulated, the UPS is compromised and autophagy is induced to control the optineurin levels .
Optineurin has different domains through which it can interact with different proteins. It contains putative domains such as C-terminal zinc finger, leucine zipper domain , a LIR domain , a NEMO-like domain , UBD domain , and various coiled-coil motifs . In Figure 2, optineurin is shown and compared with other adaptor proteins involved in selective autophagy.
Optineurin can participate in different biological activities because it has multiple domains, which mediate the interaction with other proteins. For example, optineurin can interact with Rab8 [83–85], transferrin receptor , serine/threonine kinase receptor-interacting protein 1 (RIP) , ubiquitin , and Myosin VI [61, 84], among others. The interaction of optineurin with myosin VI [84, 89] is mediated by the UBD domain, and this interaction is important in the fusion of secretory vesicles with the plasma membrane . Also, it has been described that macrophages from patients with Crohn’s disease where optineurin was under-expressed fail to secrete pro-inflammatory cytokines , which suggest that optineurin can also be involved in the vesicular transport of the autophagosomes.
As it was mentioned, the importance of optineurin in selective autophagy relies on their UBD and LIR domains, through their interaction with specific cargo and the autophagy machinery respectively. However, it has been reported that optineurin can recognize a target like a superoxide dismutase 1 and huntingtin protein by an ubiquitin-independent pathway and degrade protein aggregates through autophagy , and this recognition was related to the C-terminal coiled-coil domain of optineurin.
LIR domain mediates the interaction of optineurin with autophagy machinery. The phosphorylation of serine 177 on LIR domain by TANK-binding kinase 1 (TBK1) increases the affinity of optineurin to LC3/GABARAP proteins [81, 93]. After the dominant phosphorylation at serine 177, optineurin forms a strand with the beta-strand 2 of LC3B and phenylalanine 178 and isoleucine 181 are inserted into a hydrophobic pocket on the LC3B . On the other hand, the isomers of LC3 and the proteins of the GABARAP family interact with the machinery involved in autophagosome elongation, which is recruited to LC3/GABARAP-optineurin. Then, autophagy-related protein ATG4 is recruited to cleavage at the C-terminal of LC3/GABARAP and exhibits phenylalanine and glycine amino acids, which participate in the conjugation of LC3/GABARAP with phosphatidylethanolamine (PE)  to complete autophagosome formation finally.
Mitochondria are important and dynamic organelles, depending on energetic requirements of the cells, mitochondria can undergo cycles of fusion and fission . When mitochondria are damaged, they suffer an increase in the rate of fission, and this results in their fragmentation. Damaged and fragmented mitochondria are removed via mitophagy [28, 96]. The role of optineurin in mitophagy has been recently studied. Mitophagy requires the interaction with other proteins. First, damaged mitochondria are marked with ubiquitin by Parkin and PINK1. Both proteins act in the ubiquitination of Mitofusin 1 and Mitofusin 2 when mitochondrial depolarization was induced by carbonyl cyanide-m-chlorophenylhydrazone (CCCP) treatment . When mitochondria become depolarized, PINK1 accumulates on the mitochondrial outer membrane and phosphorylates to Mitofusin 2, this allows their interaction with inactive Parkin, and the subsequent activation of Parkin by PINK1 activates the Parkin ubiquitin ligase activity . This ubiquitination allows the interaction of optineurin with ubiquitinated mitochondria through its UBD domain, and this recognition is similar to p62 and NIX . After this initial recognition, optineurin recruits autophagy machinery around damaged mitochondria to capture it into the autophagosome .
Xenophagy has been considered as an innate immune response against intracellular infections. Xenophagy guided by optineurin has been poorly described, so it represents an interesting and wide field of study. It has been described that xenophagy mediated by optineurin participates in the intracellular control of
Due to the role of optineurin in the capture of unnecessary or damaged organelles, the lack or the deficiency of optineurin has been associated with different pathologies such as amyotrophic lateral sclerosis , Paget’s disease of bone , normal tension glaucoma, and primary open-angle glaucoma .
Valosin-containing protein (VCP/97)—also called Cdc48p in yeast, p97 in Xenopus, CDC-48 in
Currently, autophagy is an attractive area of investigation. It has been recognized the participation of autophagy in homeostatic cellular functions, such as clearance of damaged organelles, misfolded proteins, and microorganism, among others. Scientists have focused on describing the molecular mechanisms responsible for the autophagy. Now, we know that autophagy, far from beginning a random pathway, is a mechanism that elegantly regulates and is highly orchestrated by several proteins. Some proteins have been identified as bridges between the cargo and nascent phagophore, and recently studies are in process to know how these proteins are working and how to interact with the complex autophagy machinery. Several of these proteins share some structural characteristics, such as LIR domain, which allow the direct interaction with LC3 protein. However, recently, studies have identified new proteins that participate in selective autophagy but lack LIR domain, for example, VCP/p97 and Alfy. The studies to know the precise mechanisms of interaction of these proteins are in process. The understanding of the molecular mechanism that governs the autophagy represents an interesting field because many of these molecules could be manipulated to recover the cellular homeostasis in several pathologies, where autophagy is involved.
BEGP received fellowships from COFAA, EDI, and SNI. KLP, NSCJ, HIAO, and SLBU would like to acknowledge CONACYT and BEIFI for their fellowships. This work was supported by CONACYT (22001) and SIP/IPN 20160248.
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