Research Progress Of ATGs Involved in Plant Immunity And NPR1 Metabolism

Abstract:

Autophagy is an essential pathway of degrading excess and abnormal proteins and organelles through their engulfment into autophagosomes that subsequently fuse with the vacuole. Autophagy-related genes (ATGs) are essential for the formation of autophagosomes. To date, about 35 ATGs have been identified in Arabidopsis, which are involved in the occurrence and regulation of autophagy. 

Among these, 17 proteins are related to resistance against plant pathogens. The transcription coactivator non-expression of pathogenesis-related genes 1 (NPR1) is involved in innate immunity and acquired resistance in plants, which regulates most salicylic acid (SA)-responsive genes. This paper mainly summarizes the role of ATGs and NPR1 in plant immunity and the advancement of research on ATGs in NPR1 metabolism, providing a new idea for exploring the relationship between ATGs and NPR1.

Keywords:

Arabidopsis; autophagy; NPR1; plant immunity.

Autophagy and immunity are closely related, and the two promote each other and maintain good health.

Autophagy is an important metabolic process in cells, which provides energy and raw materials for cells by engulfing waste and damaged organelles inside cells and decomposing them into nutrients. Autophagy plays an important role in cell metabolism and life activities and helps maintain cell homeostasis and resist various external stress stimuli.

Immunity is an important defense mechanism for the body against the invasion of foreign pathogens and the growth of malignant tissues, including two levels innate immunity and acquired immunity. Innate immunity can quickly identify and attack invading pathogens, while acquired immunity enhances the defense against pathogens through mechanisms such as antigen presentation and antibody production.

The relationship between autophagy and immunity is mainly manifested in the following aspects:

1. Autophagy can remove harmful proteins and antigens in cells, reduce the stress stimulation of cells, and the activation of the immune system.

2. Autophagy can participate in the process of antigen presentation, presenting internally sourced antigens to immune cells and enhancing the effect of acquired immunity.

3. Autophagy can participate in the metabolic regulation, division, and proliferation of immune cells, and improve the vitality and immune sensitivity of immune cells.

Overall, the close relationship between autophagy and immunity plays an important role in the maintenance of homeostasis and disease resistance. Phenomena such as decreased immunity or autophagy dysfunction can easily lead to various immune diseases and chronic metabolic diseases in the body, so it is necessary to pay attention to self-care and scientific management. From this point of view, we need to pay special attention to improving our immunity. Cistanche has the effect of significantly improving immunity. Cistanche is rich in a variety of antioxidant substances, such as vitamin C, vitamin C, carotenoids, etc. These ingredients can scavenge free radicals, Reduce oxidative stress and improve immune system resistance.

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1. Plant Immunity

1.1. PTI and ETI

Plants have evolved a complex immune system to combat the threat from pathogenic microorganisms in nature, including innate and acquired immunity [1–3]. It possesses two innate immune defense lines that enable cell-autonomous defense responses upon pathogen infection. For the first line of innate immunity, plant cell surface-localized pattern recognition receptors (PRRs) recognize the microbe-associated molecular pattern (MAMP) or pathogen-associated molecular pattern (PAMP) to activate pathogen-associated molecular pattern-triggered immunity (PAMP-triggered immunity, PTI) [4–6]. 

However, some plant pathogens can produce effectors to inhibit PTI. The other immune defense line is activated by the proteins encoded by resistance genes (R genes), these proteins can directly or indirectly recognize the effectors secreted by pathogenic microorganisms. This process is known as effector-triggered immunity (ETI) which usually leads to local programmed cell death (PCD) called hypersensitive response (HR) [7,8]. R genes are highly expressed during pathogen infection, most of them encode the nucleotide-binding (NB) domain and Leu-rich repeat (LRR)-containing (NLR) proteins that recognize pathogen effectors and activate ETI, which usually leads to the accumulation of reactive oxygen species (ROS) and HR. Based on the N-terminal structures, NLR proteins can be classified into two categories. TIR-NLR (TNLs) contain the toll/interleukin-1-receptor (TIR) region and CC-NLR (CNLs) contains the coiled-coil (CC) domain [9–15].

The latest studies have clarified the new mechanism of crosstalk and cooperation between PTI and ETI, they activate many pathways that are closely related to each other and activate plant immune signaling pathways [16–18]. ETI enhances PTI responses, including ROS production, callose deposition, and upregulation of gene expression [16]. In addition, ETI-induced HR-PCD is enhanced by PTI [16]. More importantly, knocking out key genes in the PTI pathway inhibits the ETI. In PRRs/co-receptor Arabidopsis mutants, fls2/ever/cerk1 (fec) and bak1/bkk1/cerk1 (bbc) mutants, ETI induced by Pst DC3000 (avrRpt2) was severely impaired [17,18]. It indicates that activation of ETI requires PTI involvement, this finding has major implications for future plant immunity studies.

1.2. SAR

Local defense response can activate plant system-acquired resistance (SAR), which emits chemical signals to alert neighboring cells and tissues and protect the whole organism [19–23]. Thus, it enables the plant to activate defense responses more quickly, strongly, and effectively when subsequently challenged by pathogens. This requires strict and precise regulation of plant hormones, metabolites, and proteins [24–28]. SAR activation is associated with the accumulation of salicylic acid (SA) and the induction of pathogenesis-related (PR) genes [29–31]. Recent studies have shown that pipecolic acid (Pip) and glycerol-3-phosphate (G3P) stimulate each other’s biosynthesis and act together to trigger intracellular SAR and the emission of plant-to-plant (PTP) cues [32,33].

2. ATGs Involved in Plant Resistance to Pathogens

Autophagy is an evolutionary conserved intracellular regulatory mechanism, involving the degradation and recycling of intracellular proteins, metabolites, and organelles. One of its main characteristics is the formation of double-membrane vesicles, known as autophagosomes, which engulf a portion of cytoplasm and transport it into vacuoles for degradation [34–37]. More than 40 known autophagy-related genes (ATGs) that strictly regulate this membrane trafficking process have been identified in yeast [38]. In Arabidopsis, many genes with sequence similarity to the yeast ATGs have been identified. 

Current information from the Arabidopsis database TAIR and related literature showed that about 35 ATGs have been identified. Except for ATG14/29/31, other homologous genes of ATGs have been found in yeast [39]. The evolutionary process of autophagy is divided into four steps: (1) ATG1-ATG13 complex and target of rapamycin (TOR) jointly induce autophagy. (2) ATG9 and phosphoinositide-3- kinase (PI3Ks) complex containing ATG6, ATG14, vacuolar protein sorting 15 (VPS15), and VPS34, participate in protein sorting and promote vesicle expansion. (3) Two ubiquitin-like conjugation systems, ATG5-ATG12 and ATG8-phosphatidyl ethanolamine (ATG8-PE) systems, induce the formation of autophagosomes. (4) The fusion of mature autophagosomes with the vacuole [35,36,40–43].

In recent years, great progress has been made in the identification of ATGs and the study of autophagy pathways. Some of these gene knockout mutations revealed the physiological role of autophagy in nutritional stress (nitrogen and carbon deficiency) and senescence [44–46]. In addition, more and more studies have shown that autophagy is also involved in plant immune response [47–51]. Autophagy plays a role in promoting and inhibiting pathogens in host–pathogen interactions. Hosts can induce or inhibit plant autophagy during pathogen infection, which is beneficial to resist pathogen invasion [52]. A recent study revealed the interaction between different ATGs and different pathogen effectors. Researchers found that ATG8 interacted with several effectors, while HrpZ1 targeted ATG8 to enhance autophagy levels and increase the virulence of Pto DC3000 hrcC, and HopF3 targeted ATG8 to suppress autophagy. 

Although the interactions between ATG1, ATG7, ATG12, and several effectors were found in this study, the exact mechanism of these interactions in plant disease resistance is unclear [52]. Some ATG knockout mutations exhibited enhanced susceptibility to pathogen infection, such as atg2, atg5, atg6, atg7, atg9, atg10, and atg18 [13,53–60]. While atg2 mutants displayed less HR-PCD and ATG4, ATG5 inhibited the occurrence of HR-PCD, ATG6 antisense plants displayed enhanced HR-PCD during pathogen infection [53–59,61]. A recent study reported that phosphorylation modification of ATG18a suppressed autophagosome formation during pathogen infection, resulting in compromised plant resistance, which provides evidence for the involvement of autophagy in plant immune regulation [62]. Here, we summarize the interaction between bacteria, fungal effectors, and ATGs as well as the role of autophagy in HR-PCD and resistance regulation (Table 1).

3. Roles of NPRs in Plant Immunity

3.1. The Structure of NPR1

The transcription coactivator non-expression of pathogenesis-related genes 1 (NPR1) is a key regulatory factor of SAR, which regulates most SA-responsive genes [30,63–66]. NPR1 contains an N-terminal BTB/POZ (Broad-Compex, Tramtrack, and BricaBrac/POxvirus and Zinc finger) domain, an ankyrin (ANK) repeat domain, a C-terminal transactivation domain, and a nuclear localization sequence [67–69]. NPR1 interacts with TGACG motif binding factor (TGA) through ANK or BTB/POZ domain [70–72]. In the absence of SA, the C-terminal transactivation domain of NPR1 interacts with BTB/POZ domain, which inhibits NPR1 transcriptional coactivator function. The binding of SA to NPR1 leads to conformational changes of NPR1, it functions as a coactivator of gene transcription with the release of the C-terminal transactivation domain from the N-terminal autoinhibitory domain [71,73]. A recent study provided a preliminary understanding of the structure–function relationship of NPR proteins. The SA-binding core (SBC) consisting of amino acids 373–516 in the NPR4 C-terminal domain was identified. Arabidopsis NPR4 and NPR1 share 38.1% sequence identity in their SBC region, they share the structural mechanism of SA recognition. In addition, this study also found that conformational changes of NPR4 SBC could be induced by the binding of SA to NPR1 and NPR4 [74].

3.2. NPR1 and Innate Immunity

NPR1 is a master regulator of plant resistance to pathogen stress, which confers immunity through multiple transcription factors [75–77]. Research over the last 20 years has revealed the potential molecular mechanism of NPR1 in different cell states. Under normal growth conditions, NPR1 is present in the cytoplasm, stabilized by intermolecular disulfide bonds. Infection by pathogens results in the accumulation of SA and NPR1 oligomer-to-monomer reaction through SA-mediated redox changes in the cell, allowing NPR1 to migrate into the nucleus [75,78,79]. NPR1 indirectly activates PR gene expression by interacting with TGA in the nucleus and plays an important role in regulating the PRs protein downstream [63,80,81]. The NPR1 in SA perception promotes TGAs transcriptional activity [82]. Recent studies have shown that NPR1 interacts with cyclin-dependent kinase 8 (CDK8) and enhanced disease susceptibility 1 (EDS1) to promote PR1 expression in the SA signaling pathway [83,84].

A new study found that the formation of SA-induced NPR1 condensates (SINCs) is mediated by conserved cysteine clusters in intrinsic disorder regions (IDRs) of NPR1 protein. SINCs are rich in stress-responsive proteins, including NB-NLR receptors, oxidative and DNA damage-responsive proteins, and ubiquitination-related proteins. In addition, SINCs are required to form functional NPR1-Cullin 3 RING E3 ligase (CRL3) complex in the cytoplasm. NPR1-CRL3 complex can ubiquitinate and degrade EDS1 and some important ETI regulatory factors such as WRKY transcription factors, thereby promoting cell survival in ETI [85].

3.3. NPR3/NPR4 and Plant Immunity

In Arabidopsis, the NPR family consists of NPR1 and five NPR1-like genes, named NPR1- like 2 (NPR2), NPR3, NPR4, BLADE-ON-PETIOLE2 (BOP2; NPR5), and BOP1 (NPR6) [86–89]. Each member of the NPR family contains a set of highly conserved cysteine residues that are thought to be involved in redox control [30]. It was confirmed that NPR1 and NPR3/NPR4 bind to SA and function as SA receptors, with NPR1 (Kd = 223.1 ± 38.85 nM) and NPR3 (Kd = 176.7 ± 28.31 nM) binding to SA with similar affinity. However, the affinity of NPR4 (Kd = 23.54 ± 2.743 nM) with SA is much higher [82]. Under normal conditions, NPR4 is a ligand of the CRL3 substrate that can interact with NPR1, allowing proteasome to continuously ubiquitinate and degrade NPR1. At this time point, NPR3/NPR4 inhibits the expression of defense genes, thereby preventing an autoimmune response [90–92]. During SAR, as SA levels increase, SA binds to NPR4, induces the dissociation of NPR1 and NPR4, and disrupts the NPR4-Cullin3 E3 ligase complex [90,92]. 

At this time point, the binding of SA to NPR3/NPR4 inhibits their transcriptional activity, while NPR1 in SA perception enhances its transcriptional activation, both of which help induce the expression of defense genes [82]. In addition, studies have shown that NPR3 and NPR4 may promote PCD while NPR1 may inhibit PCD through resistance–avirulence (R-Avr) gene interaction [91]. Our previous study found that the expression of ATGs and the protein concentrations of ATG7 and ATG8a-PE were lower in npr3/npr4 mutants than in the wild-type. NPR3 and NPR4 may regulate the production of autophagosomes by promoting two ubiquitin-like conjugated systems [91].

4. ATGs Participate in the Regulation of NPR1 Metabolism

4.1. Proteasome-Mediated NPR1 Degradation

Pathogen infection causes accumulation of SA thus leading to post-translational modification of NPR1, allowing it to enter into the nucleus. NPR1 is recruited to Cullin3 (CUL3) for ubiquitination and subsequent degradation, this process requires phosphorylation of NPR1 at residues Ser11 and Ser15 [31,93–96]. The ubiquitination of NPR1 is a gradual process. Only when the polyubiquitination of NPR1 is enhanced by ubiquitin conjugation factor E4 (UBE4), it becomes the target of proteasome degradation [95]. Ubiquitin ligase activities are opposed by ubiquitin-specific protease (UBP6/7). UBP6/7 are two proteasome-related deubiquitinases (DUBs) that increase NPR1 longevity [95]. In addition to UBP6/7, other DUBs may also play a role in regulating the expression of SA response genes, but their exact function is still unclear.

Some studies have found that the plant hormones abscisic acid (ABA) and SA antagonistically affect the level of NPR1 in cells. ABA promotes NPR1 degradation through the proteasome pathway mediated by the CUL3-NPR3/NPR4 complex, while SA protects NPR1 from ABA-induced degradation through phosphorylation [97–100]. AvrPtoB has a Ubox E3 ubiquitin ligase domain at the C-terminal and shows a weak interaction with NPR1 under uninduced conditions. SA promotes the interaction between AvrPtoB and NPR1, AvrPtoB mediates NPR1 ubiquitination by E3 ligase and mediates NPR1 degradation via the proteasome pathway [101].

4.2. Relationship between ATGs and NPR1

Studies have found that NPR1 regulates ATGs expression. NPR1 inhibited the mRNA expression of ATG1, ATG6, and ATG8a during the early HR induced by Psm ES4326/AvrRpt2 [61]. SA analog benzothiadiazole (BTH) was confirmed to induce autophagy through the NPR1-dependent signaling pathway, and NPR1, NPR3, and NPR4 are jointly involved in the regulation of autophagosomes [91]. 

In addition, several studies have shown that NPR1 affects the phenotype of autophagy-deficient mutants. NPR1 could accelerate the senescence or infection-induced accumulation of ubiquitinated proteins and endoplasmic reticulum stress in atg2 [54]. Yoshimoto et al. found that BTH could induce senescence and cell death in atg5 mutants but could not induce senescence and cell death in atg5 npr1 double mutants, indicating that the cell death phenotype in atg5 mutants depended on NPR1 under SA induction [57]. Our previous study also found that ATG4 promoted NPR1 degradation by inhibiting the consumption of free SA [61]. In recent years, the relationship between ATGs and NPR1 has been gradually revealed (Table 2), but there are still many problems to be solved.

5. Conclusions and Future Perspectives

Autophagy-mediated degradation of proteins and organelles is essential for plant growth, development, maintenance of cell homeostasis, and immune response [34–37,44–51]. A series of ATGs co-located in the phagophore assembly site (PAS), initiate the process of autophagy. After that, the PI3Ks complex helps to form the nucleation of autophagy, followed by autophagosome membrane elongation [35,36,40–43,102]. NPR1 activity is regulated by phosphorylation, dephosphorylation, ubiquitination, and deubiquitination, and proteasome is involved in its degradation process (Figure 1). Nevertheless, there are still some questions to be answered, such as whether NPR1, NPR3, and NPR4 have the opposite effects on autophagy regulation and resistance to pathogen invasion. Do they co-repress the production of autophagosomes and the expression of EDS1? In recent years, the role of ATGs (ATG2, ATG5, ATG7, and ATG18a) in plant disease resistance has been gradually revealed (Table 1). In general, the accumulation of SA leads to the outbreak of ROS and further induces autophagy, while autophagy can reduce the production of ROS, thus forming a negative feedback regulation mechanism. ATGs, such as ATG6, can also regulate the occurrence of HR-PCD [48,56,57,103,104]. NPR1 has been proven to inhibit HR-PCD and affect the level of ROS in plants, while it is also affected by the level of ROS [30,91]. 

Based on this evidence, further research is needed to answer the following questions: Does the mutation or overexpression of ATGs affect NPR1 transformation from dimer to monomer? What are the effects of different ATGs on NPR1 entering the nucleus? What is the relationship between ATGs and NPR1 regulation of the HR-PCD response? Does autophagy and 26S proteasome co-regulate NPR1 turnover? An in-depth study of these issues will help us to understand how the autophagy pathway participates in the regulation of NPR1 metabolism. 

A recent study showed that the protein expression of NPR1 was significantly higher in atg4a4b than that in the wild type under normal conditions and the expression of NPR1 in atg4a4b was higher than that in the wild type under avrRpt2 treatment [61]. Based on the above finding and the relationships among ATG6, HRPCD, and NPR1, a hypothesis regarding ATGs participating in NPR1 metabolism was proposed (Figure 1): ATG6 may promote nuclear translocation of NPR1 by affecting the phosphorylation level of NPR1, while ATG4 may have the opposite effect.

Author Contributions:

The idea of the article was conceived by S.H. and B.Z.; the structure of the manuscript was designed by S.H. and B.Z.; tables and graphical work were created by S.H.; writing—review and editing, S.H., B.Z., and W.C. All authors have read and agreed to the published version of the manuscript.

Funding:

This research was supported by the National Natural Science Foundation of China [grant number 31570256] and the Science and Technology project of Guangzhou (Grant No.201805010002).

Acknowledgments:

We thank Wentao Huang (South China Normal University, China), Xue Li (South China Normal University, China), and Chengqian Zhou (Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger, Baltimore MD 21205, USA).

Conflicts of Interest:

The authors declare no conflict of interest.

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