Degradation Mechanism of Autophagy-Related Proteins: History
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Subjects: Plant Sciences
Contributor:
Yanhui Zhou
,
Hakim Manghwar
,
Weiming Hu
,
Fen Liu

In all eukaryotes, autophagy is the main pathway for nutrient recycling, which encapsulates parts of the cytoplasm and organelles in double-membrane vesicles, and then fuses with lysosomes/vacuoles to degrade them. Autophagy is a highly dynamic and relatively complex process influenced by multiple factors. Under normal growth conditions, it is maintained at basal levels. However, when plants are subjected to biotic and abiotic stresses, such as pathogens, drought, waterlogging, nutrient deficiencies, etc., autophagy is activated to help cells to survive under stress conditions. At present, the regulation of autophagy is mainly reflected in hormones, second messengers, post-transcriptional regulation, and protein post-translational modification. 

  • autophagy-related protein
  • degradation
  • ubiquitin
  • proteasome
  • autophagy

1. Introduction

Autophagy widely exists in eukaryotic cells, which is a relatively conservative process in evolution. It is responsible for the transport of certain cytoplasmic proteins and subcellular organelles into lysosomes/vacuoles for degradation, thereby contributing to the recycling of intracellular nutrients [1][2]. In yeast and mammals, autophagy consists of three types: microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA). However, CMA is absent in plants and has been replaced by mega-autophagy [3]. Among them, the so-called autophagy usually refers to macroautophagy, which contains both selective and non-selective intracellular degradation processes [4] (Figure 1). Selective autophagy is distinguished from bulk autophagy by the use of selective autophagy receptors (SARs) [5]. Macroautophagy begins with a series of autophagy-related (ATG) proteins forming phagophore structures at the assembly site of the phagophore, and then recruiting substrate molecules, and forming autophagosome with double-layer membrane structure through the expansion and closure of vesicles. Subsequently, the outer membrane of the autophagosome fuses with the lysosomal or tonoplast membrane to release the contents into the lysosomal lumen or vacuole in the form of an autophagic body with only a single membrane, and is degraded into small molecular substances for recycling under the role of acid hydrolase [6][7][8]. Microautophagy is a process that isolates and uptakes cell components by direct enclosure with the lysosomal/vacuolar membrane [9]. Autophagy plays an important role in maintaining cellular homeostasis. Plants are exposed to many biotic and abiotic stresses, and these stresses affect plants [10][11][12][13][14][15][16]. When cells face stress conditions, such as nutrient deprivation, oxygen deficiency, and endoplasmic reticulum (ER) damage, autophagy is highly induced to maintain metabolic and energy balance [16][17][18][19]. During starvation, lysosomal activity is also improved to support autophagic flux [20].
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Figure 1. Morphological steps of microautophagy and macroautophagy in eukaryotes. Macroautophagy begins with the formation of a phagophore that encapsulates damaged organelles and discarded proteins. Then, through the extension of the vesicle forms a closed structure with a double membrane, which is called an autophagosome. Subsequently, the outer membrane of the autophagosome fuses with the lysosomal membrane (animals) or the tonoplast (yeast and plants) to release the autophagic body with only a single membrane. Finally, under the digestion of acid hydrolases, the cargoes were degraded into small molecular substances for recycling. Microautophagy is a process in which the lysosome/vacuole directly packages target substrates by membrane invagination to create the autophagic body.

2. ATG Complexes in Plants and Animals

ATG proteins play an indispensable role in the process of autophagy in plant and animal cells. According to their diverse functions in different stages of autophagy, core ATG proteins can be divided into four major complexes (Figure 2).
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Figure 2. Core protein complexes of autophagy in plants and animals. (A) The ATG1/ATG13 protein kinase complex. When plants are under nutrient-rich conditions, TOR kinase hyperphosphorylates ATG13. While plants are placed in nutrient starved conditions, the TOR kinase is inactivated, resulting in the dephosphorylation of ATG13, which binds tightly to ATG1. Then, the ATG1 kinase activity is activated and autophosphorylation occurs to form the ATG1, ATG11, ATG13, and ATG101 complex, which results in upregulating autophagy. (B) The ATG9/2/18 transmembrane complex and PI3K complex. ATG9 delivers membrane source and mediates the extension of phagophore membrane. ATG2 and ATG18 play a synergistic role in this process. The PI3K protein complex promotes the nucleation of vesicles, which include ATG6, ATG14, VPS34, VPS15, and PI3P. (C) The ATG5-ATG12 and ATG8-PE ubiquitin-like conjugating systems. ATG12 was transferred to the target protein ATG5 with the help of ATG7 and ATG10. Subsequently, the ATG5-ATG12 complex combines with ATG16 to form an oligomeric complex, which participated in the esterification of ATG8. During the covalent binding stage of ATG8-PE, the cysteine protease ATG4 cleaves the C-terminus of ATG8. Subsequently, ATG8 is activated by ATG7 and transferred to ATG3 through a thioester bond. At last, with the help of ATG5-ATG12-ATG16 conjugate, ATG8 forms an ATG8-PE adduct with phosphatidylethanolamine. (D) Core ATG proteins of plants and mammals in four complexes.

3. Degradation of Yeast Autophagy-Related Proteins

Among yeast autophagy-related proteins, the degradation mechanisms of the transmembrane proteins Atg9 and Atg32 have been discovered. The content of Atg9 in cells is known to be a key factor in determining the number of phagosomes [21]. Under normal growth conditions, Atg9 is ubiquitinated at the Lys113, Lys121, and Lys138 sites and subsequently degraded by the proteasome at peripheral sites away from PAS by Met30, which is one of the substrate recognition components of the ubiquitin ligase SCF complex (Skp, Cullin, F-box containing) (Table 1) [22][23]. When cells are under nutrient-deficient conditions, Atg9 is stabilized by Atg1 phosphorylation, thus inhibiting the degradation process, and activating the autophagy process [24].
Table 1. E3 ligases and ubiquitin chain types involved in ATGs degradation in yeast, mammalian, and plants.

Eukaryotes

ATGs

E3 Ligases

Ubiquitin Chain Types

References

Yeast

Atg9

Met30

Unknown

[23]

Atg32

Rsp5

Unknown

[25]

Mammalian

ULK1

CUL3-KLHL20

K48

[26]

BTRC

K48

[27]

TRAF3

K48

[28]

NEDD4L

K27 and K29

[29]

ATG101

HUWE1

K48

[30]

WIPI2

HUWE1

Unknown

[31]

ATG14L

ZBTB16-CUL3-Roc1

Unknown

[32]

BECN1

NEDD4

K11

[33]

RNF216

K48

[34]

CUL3-KLHL20

Unknown

[35]

CUL3-KLHL38

K48

[35]

TRAF6

K63

[36]

VPS34

UBE3C

K29/K48 branched

[37]

FBXL20-CUL1-SKP1

Unknown

[38]

ATG16L1

Gigaxonin

K48

[39]

LC3B

BIRC6

Single ubiquitin

[40]

ATG3

PTK2

Unknown

[41]

Plants

ATG6

SINAT1/2

Unknown

[42]

ATG13

SINAT1/2

K48

[43]

SH3P2

XopL

Unknown

[44]

4. Degradation of Autophagy-Related Proteins in Metazoa

4.1. Degradation of ULK Complex Components

In mammals, the ULK complex includes four parts: ULK1/2, ATG13, RB1CC1/FIP200, and ATG101. Among them, ULK1 plays a major role in autophagy [45]. The level of ULK1 is regulated by E3 ubiquitin ligase and USPs. Under prolonged starvation, autophosphorylation of ULK1 at the Ser1042/Thr1046 site facilitates its recruitment to Kelch-like (KLHL) 20 for ubiquitination and protein degradation as a substrate for the Cullin3 (Cul3)-KLHL20 ubiquitin ligase, thereby preventing cell unrestricted activate autophagy. In addition, KLHL20 also coordinates the degradation of ATG13 through an indirect mechanism [26]. Cancer can hijack the protective function of autophagy to promote tumorigenesis [46]. In breast cancer cells, mitogen-activated protein kinase (MAPK) 1/3 kinases promote its binding to the E3 ligase BTRC by phosphorylating ULK1 at multiple sites, triggering proteasomal degradation of K48-linked ULK1 ubiquitination, ultimately attenuating mitophagy and promoting breast cancer bone metastases [27]. Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF family with E3 ligase activity. In macrophages, TRAF3 mediates K48-linked ULK1 ubiquitination and proteasomal degradation, and the TRK-fused gene (TFG)-TRAF3 complex is able to interfere with TRAF3-ULK1 interaction to stabilize ULK1 in response to lipopolysaccharide (LPS)-induced pyroptosis [28]. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is an E3 ubiquitin ligase containing a HECT domain. When cells need to endure starvation, NEDD4L ubiquitinates ULK1 at the Lys925 and Lys933 sites. It induces its degradation by the proteasome, thus autophagy is calibrated to optimal levels to ensure the survival of cells. Interestingly, NEDD4L-mediated ubiquitination of ULK1 is not a canonical K48 linkage, but a K27 and K29 linkage [29].

4.2. Degradation of ATG9 Complex Components

The mammalian ATG9 complex contains four ATG18 homologs, namely, WIPI 1-4. Studies have shown that WIPI2 can associate the phagophore with ER [47] and play a role in cellular antibacterial autophagy [48]. Under basal cellular conditions, mTORC1 mediates the phosphorylation of WIPI2 at the Ser395 site, thereby enhancing the specific interaction of WIPI2 with HUWE1, promoting the ubiquitination and proteasomal degradation of WIPI2, and inhibiting the degree of autophagy [31].

4.3. Degradation of PI3K Complex Components

In mammals, the autophagy-specific PI3K complex I consists of four proteins: VPS34, VPS15, BECN1, and ATG14L [49]. Ubiquitination and proteasomal degradation of ATG14L are regulated by the E3 ubiquitin ligase complex zinc finger and BTB domain containing 16 (ZBTB16)-CUL3-Regulator of cullins 1 (Roc1). Under normal nutritional conditions, inhibition of G-protein-coupled receptors (GPCRs) activates glycogen synthase kinase-3β (GSK-3β). It mediates ZBTB16 phosphorylation to promote its autoubiquitination, which in turn upregulates ATG14L levels to activate autophagy [32]. In host cells, Streptococcus pneumoniae (Sp) releases choline binding protein C (CbpC) to form the ATG14L-CbpC-sequestosome 1 (SQSTM1)/p62 intracellular complex, promoting autophagy-dependent degradation of ATG14L, which results in inhibiting autophagosome-lysosome fusion and bactericidal autophagic degradation, increasing bacterial survival [50].
BECN1, the first tumor-associated ATG protein discovered in mammals, plays a role in the formation, elongation, and maturation of autophagosomes [51][52]. Different E3 ligases play various roles in regulating BECN1 activity by binding to specific types of ubiquitin chains. NEDD4 and Ring finger protein 216 (RNF216) modify BECN1 through K11, K63 and K48-linked polyubiquitination chains, respectively, which mediates the BECN1 degradation in a proteasome-dependent manner and negatively regulates autophagy [33][34]. Similarly, CUL3-KLHL20-mediated ubiquitination of BECN1 is primarily responsible for the termination of autophagy during prolonged starvation, whereas CUL3-KLHL38-mediated BECN1 K48-linked ubiquitination prevents autophagy under normal conditions [35]. TRAF6 acts as an E3 ligase to trigger the K63-linked ubiquitination of BECN1, while the deubiquitinating enzyme A20 inhibits the ubiquitination of BECN1 [36]. Furthermore, tripartite motif 59 (TRIM59) mediates K48-linked ubiquitination and proteasomal degradation of TRAF6, which results in affecting TRAF6 to ubiquitinate BECN1, regulating the initiation of autophagy [53].

4.4. Degradation of the ATG12-Conjugation System Components

The ATG12-conjugation system includes ATG5, ATG7, ATG10, ATG12, and ATG16L1. ATG12 is a member of the ubiquitin-like protein (UBL) family, which consists of about 20 members [54]. Free ATG12 is highly labile and can be targeted for proteasomal degradation through ubiquitin-dependent or ubiquitin-independent mechanisms [55]. ATG5 is a ubiquitin-like ligase that is conjugated by ATG12 [56]. In Lepidoptera, there is an interaction between ATG1 and ATG5, and Spodoptera litura ATG1 (SlATG1) promotes the degradation of ATG5 [57]. In cardiomyocytes, the immunoproteasome β5i subunit interacts with ATG5 to promote the ubiquitination and degradation of ATG5, thereby inhibiting autophagy and leading to cardiac hypertrophy [58]. Moreover, saturated fatty acid palmitate induces ER stress and degrades ATG5 protein through the ER-associated protein degradation (ERAD) pathway, consequently inhibiting autophagy and inducing apoptosis [59].
ATG16L1 interacts with ATG5, which stimulates the ATG8-PE coupling reaction [60]. Gigaxonin (GAN)-E3 ligase ubiquitinates ATG16L1 through K48-type ubiquitin chain polymerization, driving its degradation, thereby controlling the steady-state level of ATG16L1 to ensure fine-tuning of autophagy activation. Loss of GAN leads to the formation of ATG16L1 aggregates that impair phagophore elongation, inhibiting autophagic flux [39].

4.5. Degradation of the LC3-Conjugation System Components

In mammalian cells, LC3, GABA type A receptor-associated proteins (GABARAPs), GATE16, and ATG8L exist as yeast Atg8 homologs [61][62]. All of them can be used as autophagosome markers. Under normal conditions, BRUCE acts as an autophagy inhibitor, promoting proteasomal degradation of LC3-I, which results in reducing LC3-II levels and autophagy [63]. Similarly, UBA6 and BIRC6 act synergistically as E1 and E2/E3 enzymes, respectively, for the monoubiquitination and proteasomal degradation of LC3B, which protects cells from cell death caused by excessive autophagy [40][64]. In addition, circumsporozoite protein (CSP) downregulates LC3B through the UPS pathway, but the mechanism involved is unclear [65].
ATG3 acts as an E2-like enzyme in LC3 lipidation. It can autocatalyze itself to form a complex with ATG12 to promote mitochondrial homeostasis [66][67]. Under DNA damage conditions, protein tyrosine kinase 2 (PTK2) phosphorylates ATG3 at the Tyr203 site and promotes the degradation of ATG3 through the ubiquitin-dependent proteasome pathway, resulting in positively regulating the activity of cancer cells [41].

5. Degradation of Plant Autophagy-Related Proteins

Up to now, more than 40 kinds of ATG proteins and their related regulatory proteins have been identified in plants [68], mainly from the analysis of yeast autophagy-deficient mutants, but their degradation mechanisms are poorly understood. In Arabidopsis thaliana, the turnover of ATG1 and ATG13 is strongly and specifically regulated by nutrition, which closely links autophagy with plant nutritional conditions. During the period of fixed carbon/nitrogen limitation, the levels of ATG1 and ATG13 decreased sharply, but they could be reversed again during refeeding. Studies on A. thaliana mutants that damage autophagy or 26S proteasome show that both degradation pathways are involved in their degradation, but autophagy is more directly involved. Under the condition of limited nutrition, ATG1 and ATG13 combine with autophagic-like cytolytic structures and finally transfer to vacuoles together with autophagosomes for degradation [69].
In addition, Liu et al. [70] found a similar phenomenon in their study of ATG14 and its associated PI3K complex. By expressing GFP-ATG14b in atg7 and atg14a atg14b mutants, it was found that there was still free GFP in atg14a atg14b mutants, which indicated that ATG14 was degraded, unlike the intact GFP-ATG14b fusion in atg7 mutants with autophagy defects. Next, after N starvation treatment, co-localization of atg14a atg14b mutant roots expressing both mCherry-ATG8a and GFP-ATG14b revealed that ATG14 was bound to autophagic membranes [70]. Thus, similar to ATG1 and ATG13, ATG14 is degraded by the autophagic pathway through associating with the autophagic bodies.
The effect of ubiquitination of autophagy-related protein on autophagy has been widely studied in mammals, but less in plant cells. In plants, a single ubiquitin molecule can form a polyubiquitin chain at a certain site in a target protein (polyubiquitination) or be attached to multiple lysine residues (multi-monoubiquitination). In A. thaliana, K48 is commonly used to form polyubiquitin chains [71]. Qi et al. [42][43] successfully studied the turnover of ubiquitination modification of ATG6 and ATG13 in A. Thaliana (Figure 3). Under different nutritional conditions, as molecular adaptors, A. thaliana TRAF1a and TRAF1b interacted with Ring finger E3 ligase seven in absentia of Arabidopsis thaliana 1 (SINAT1)/SINAT2 and SINAT6 to regulate the turnover of ATG6 and ATG13. Among them, SINAT6 contains only a short truncated Ring finger domain compared to SINAT1 and SINAT2 [72]. Under nutrient-rich conditions, A. thaliana TRAF1a and TRAF1b interact with SINAT1 and SINAT2 to mediate ubiquitination and degradation of ATG6. However, under conditions of nutrient deprivation, starvation-induced accumulation of SINAT6 reduces the binding of SINAT1 and SINAT2 to ATG6, stabilizes ATG6 levels, and activates autophagy [42].
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Figure 3. Degradation mechanisms of ATG6 and ATG13 in plants. During nutrient-rich conditions, the TRAF1s-SINAT1/SINAT2-ATG6 and TRAF1s-SINAT1/SINAT2-ATG13 TRAFasomes regulate the ubiquitination and proteasomal degradation of ATG6 and ATG13, which results in inhibiting autophagy. Under the condition of nutrient starvation, SINAT6 accumulates to form the TRAF1s-SINAT6-ATG6 and TRAF1s-SINAT6-ATG13 TRAFasomes, which maintain the stability of ATG6 and ATG13. Furthermore, ATG1 kinase phosphorylates TRAF1s to increase its stability.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23137301

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