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Autophagy and plant innate immunity. 穆颖 张晓丽. 1 、 Plant innate( 先天的,固有的) immunity is often associated with specialized programmed cell death at or near the site of pathogen infection. 。 . 2 、 role of autophagy in plant innate immunity 。

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Autophagy and plant innate immunity


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slide2

1、Plant innate(先天的,固有的) immunity is often associated with specialized programmed cell death at or near the site of pathogen infection.。

2、role of autophagy in plant innate immunity。

autophagy is observed in healthy and dying plant cells,whether autophagy plays a protective or a destructive role during an immune response?

slide3

autophagy, an evolutionarily conserved process of bulk protein and organelle turnover, was shown to play an important role in limiting cell death initiated during plant innate immune responses.

Autophary :

For a cell to maintain homeostasis, there needs to be constant turnover of macromolecules to adjust to the cellular changes necessitated by responses to the immediate environment. Autophagy, a Greek word meaning to ‘eat oneself’, is needed for non-specific protein and organelle turnover.

It can be induced by multiple stress factors including cellular damage, lack of nutrients or pathogen attack .

There are different types of autophagy, including biosynthetic autophagy as seen in yeast in the trafficking of the vacuolar protein aminopeptidase during cytoplasm-to-vacuole transport (CVT) and several degradative types including macroautophagy .

We will use autophagy to refer to bulk degradation mediated by macroautophagy.

slide4

Autophagy is visually characterized by the formation of a double-membrane bound structure called the autophagosome (Fig. 1).

PAS:preautophagosomal structure

ATG gene : required for autophagosome formation and for proper autophygic activity

slide6

Autophagy in plant :

Regulation of PCD(programmed cell death) initinated during plant innate immunity by autophage

Autophagy and viability: pro-survial or pro-death

Autophagy as an antimicrobial defence mechanism

slide7

Now we use arabidopisis(拟南芥)in example:

In plants, autophagy has been associated with leaf

senescence(叶片衰老) .

slide8

Extensive analysis of the Arabidopsis genome has identified at least 36 genes with significant homology to yeast ATG genes (Table 1).

Two main questions arise when examining the Arabidopsis

ATG-like (AtATG) genes:

1. Why have plants retained ATG genes (for example ATG13) not required for autophagy in other higher eukaryotes

2. why are there multiple copies of ATG-like genes (ATG8

and ATG18) in the Arabidopsis genome?

slide9

Table 1. Microarray analysis of the known or putative autophagy

GENEVESTIGATOR

Arabidopsis using .

genes from

Autophagy genes M. persicae P. syringae -N PCD

ATG1

AT1g49180 + – – + + +

AT2g37840 + + + –

AT3g53930 + + + + +

AT3g61960 NC + + +

ATG3

AT5g61500 + + + +

ATG4

AT2g44140 + + + + – NC

AT3g59950 NC + + + +

ATG5

AT5g17290 + + NC + +

slide10

Intriguingly, the Arabidopsis genome retains a homologue of ATG13 while this gene has been lost in humans, Drosophila (果蝇)and Caenorhabditis elegans.

The association/disassociation of ATG13 with ATG1 is

ought to play a key role in initiation of autophagy in yeast

Some higher eukaryotes including humans have retained the ability to form autophagosomes and regulate autophagy despite lacking ATG13.

This suggests that ATG13 is not needed for autophagy outside of yeast or that an unrelated protein retains the function of ATG13 in these higher eukaryotes.

第八张

slide11

Despite the strong sequence similarities, some AtATG (拟南芥里的ATG-like Gene) genes are unable to complement yeast deletion strains.

This may because that :

the ATG-like genes from affecting autophagy in its respec-

tive organism.

It has been demonstrated that some mammalian ATG-like genes are functionally equivalent to their respective yeast counterparts and are required for autophagy in mammals despite not being able to complement yeast mutants.

slide12

Arabidopsis atg3, atg7, atg5, atg9 and atg13 mutants have identical developmental phenotypes .

For example:

AtATG7 knockout causes a senescence defect and hyper-

sensitivity to nitrogen and carbon starvation, consistent with a

requirement for autophagy during nutrient limitation in yeast and other higher eukaryotes .

The senescence phenotype can be rescued with a wild-type copy of AtATG7 but not with AtATG7 mutant that effect catalytic activity and autophagosome formation

regulation of pcd initiated during plant innate immunity by autophagy
Regulation of PCD initiated during plant innate immunity by autophagy

Recent studies from plants and animals indicate that the autophagic machinery is involved in innate and adaptive immunities

slide14

Although autophagy is known to be active at basal levels

under normal physiological conditions, it can be stimulated by a plethora(过多的) of stresses including cellular damage, nutrient starvation and pathogen infection .

plant ATG genes are upregulated during nitrogen starvation consistent with their function in senescence and hypersensitivity to nutrients

Interestingly, these genes are also regulated during defence responses to pathogens.

Several AtATG genes are upregulated following infection with the bacterium Pseudomonas syringae(紫丁香属假单胞菌) or the aphid(蚜虫) Myzus persicae (Table 1) .

With few exceptions, it is interesting to note that most of the AtATGs are upregulated during both PCD and P. syringae infection.

slide15

The most extensively studied plant innate immunity involves recognition of pathogen-encoded avirulence(Avr) proteins by plant resistance (R) proteins. Often this R–Avr interaction leads to the hypersensitive response (HR), a form of PCD, at the site of pathogen infection.

HR-PCDis often observed as necrotic lesions and the patho-

gen is restricted to these lesions and cells immediately

surrounding it.

Therefore, it is thought that the HR-PCD functions to limit the spread of pathogen from infection sites into adjacent healthy tissue .

slide16

The HR-PCD initiated at the site of pathogen infection

must be meticulously controlled through specific mechanisms and checkpoints to minimize damage to the rest of the plant.

slide17

Recent evidence indicates that autophagy is one mechanism by which HR-PCD initiated during plant innate immunity is controlled

The tobacco N protein belongs to the TIR-NB-LRR class of R proteins and confers resistance to tobacco mosaic virus (TMV) .

The N protein specifically recognizes the 50 kDa helicase

domain of the TMV replicase protein to trigger induction of HR-PCD and restriction of virus spread.

Interestingly silencing of Beclin 1 resulted in uncontrolled HR-PCD upon TMV infection (Fig. 2). This phenotype is dependent

on a successful innate immune response because Beclin1-silenced plants infected with TMV failed to induce death in the absence of N.

slide18

Fig. 2. Beclin 1 is required to limit the spread of HR-PCD induced by TMV. Representative photographs of leaves from non-silenced control

(VIGS-Vector) and Beclin 1-silenced (VIGS-Beclin 1) plants infected with GFP-tagged TMV. Red colour in the background of GFP fluorescence in the UV illumination photographs is due to auto-fluorescence from chlorophyll.

slide19

Mammalian Beclin 1, was first identified as an interactor of the antiapoptotic protein Bcl-2 .

Beclin 1 is part of a class III PI3K/VPS34 complex required for autophagosome formation and recruitment of other ATG proteins into PAS ( 前体自噬体结构).

Interestingly, silencing of other autophagy genes including

PI3K/VPS34, ATG3 and ATG7 also resulted in uncon-

trolled HR-PCD upon TMV infection.

The requirement of Beclin 1 and other autophagy genes to

limit HR-PCD to the infection site during a plant innate

immune response indicates that autophagy may be

involved in this processes.

.

slide20

In addition, LysoTracker Red staining and electron micros-

copy data showed that autophagy is induced during the

N-mediated response to TMV not only at the site of HR-

PCD but also in the adjacent healthy tissue.

autophagy is not required for execution of PCD, but rather it is required to limit PCD to the infection site.

These results imply that there is a ‘pro-death’ signal(s) moving out of the pathogen infected area into adjacent tissues that is negatively regulated by autophagy.

slide21

However, in the Beclin 1-silenced plants, the induction of autophagy was compromised upon TMV infection.

Autophagy is not only required to limit N-TMV induced HR-PCD but also other R–Avr interactions and general elicitor induced HR-PCD. (就是说这只是一个例子)

autophagy plays a central role in regulating HR-PCD that occurs in plant immunity

autophagy and viability pro survival or pro death
Autophagy and viability: pro-survival or pro-death?

Compounding the intrigue was the discovery that Beclin-1 interacts with Bcl-2, suggesting surprising novel crosstalk between two potential cell death pathways.

However, it is still unclear exactly if and how Bcl-2 affects autophagy or how autophagy affects antiapoptotic Bcl-2 family proteins.

two hypothesis:

1、 autophagy plays a crucial role in cell survival during PCD.

2、 autophagy itself is a ‘pro-death’ process or results in cell death by regulating apoptosis.

Recent evidence suggests that both hypotheses may be correct depending on the cell type, stimuli and developmental stage.

slide23

1、It is well established that autophagy promotes cell survival

during nutrient starvation by degrading and recycling

nutrients.

2、Autophagy may also indirectly promote cell survival by retarding(阻止)or preventing apoptosis.

slide24

When autophagy is compromised genetically or pharmacologically(药理学的), HeLa cells die via an apoptotic pathway.

This death is abolished using Bcl-2 or caspase inhibitors suggesting that autophagy prolongs survival by deterring the onset of apoptosis.

slide26

autophagy itself is a ‘pro-death’ process or results in celldeath by regulating apoptosis.

slide27

Overexpression of Bcl-2 or Bcl-X in wild-type mouse embryonic fibroblasts treated with etoposide, a common apoptotic reagent, resulted in increased autophagosome formation. Autophagy mediated death seems to depend on Bcl-Xbecause elimination of

Bcl-X reduced the formation of autophagosomes and death.

In addition, Bax/Bak double-knockout mice lines were unable to induce apoptosis, yet when treated with etoposide, the cells were still able to die.

The non-apoptotic death was dependent on functional autophagic mechanisms.

autophagy as an antimicrobial defence mechanism
Autophagy as an antimicrobial defence mechanism

Mounting evidence indicates that autophagy plays an important role in the elimination of intracellular and extracellular pathogens.

slide29

In animals, recent findings indicate that autophagy is also used to combat against bacterial pathogens. Autophagy induced by nutrient starvation or by treatment with rapamycin actively inhibits the survival of the facultative intracellular pathogen Mycobacterium tuberculosis

Similarly, autophagic vesicles effectively engulf and destroy invading extracellular pathogens

such as group A Streptococcus (GAS). Autophagy-deficient atg5-/- mutant ES cells are

incapable of eliminating GAS, allowing it to survive and

Proliferate.

slide30

These results indicate that autophagy functions as an antiviral defence mechanism. The increase in virus accumulation in autophagy deficient cells suggests that ATG proteins might target cellular factors or pathways required for virus replication and spread.

slide31

It seems some bacteria have evolved effective counter-defence strategies to subvert autophagy and promote successful infection. 1、Some bacterial and viral pathogens have evolved to utilize the autophagy machinery for replication or survival inside the host cell Autophagosomal-like vesicles provide a replicative niche for a variety of pathogens including Legionella pneumophila, and Bru-

ella abortus .

2、While hiding inside autophagosomes, these pathogens eplicate and either restricts autophagosome maturation

or delay fusion with the lysosome.

3、The invasive pathogen Porphyromonas gingivalis even stimulates autophagosome formation and uses them to enter the host cells.

4、Similarly, poliovirus and mouse hepatitis virus (MHV) induce the formation of autophagosome-like double-membrane vesicles (DMV) and use them as a replicative niche.

eg: In atg5-/-ES cells infected with MHV, formation of DMV is inhibited and replication of the virus is drastically reduced indicating thatautophagy is required for efficient replication of MHV