Modulates autophagy or xenophagy in host cell

[genegodbold]

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Preferred term label

Modulates autophagy or xenophagy in host cell

Synonyms

None

Textual definition

Alteration of host autophagy or xenophagy for the benefit of the parasite.

Suggested parent term

This term could be a child under the newly proposed parent term "Modulation of host process by parasite"

Attribution

https://orcid.org/0000-0002-5702-4690

[jproesch]

@genegodbold there is some overlap here with "inhibits phagocytosis" (PATHGO_0000232) regarding xenophagy. Xenophagy could be included as a synonym for the phagocytosis terms. Is there a need for "modulates" to allow a non-inhibitory effect? Also, regarding autophagy, do you have an example for this that is distinct from xenophagy?

[genegodbold]

Hey @jproesch, Xenophagy/autophagy and phagocytosis are two different things, though they can flow together. Eukaryotic cells have specific processes that bacteria (for example) can interact with independent of phagocytic processes. Some examples:

Anaplasma translocated substrate-1: Ats-1, a T4SS effector, binds host beclin 1 (UniProtQ14457), a subunit of the class III PI3K and Atg14L which helps induce autophagy. Ats-1 localizes the host proteins beclin-1, Atg14L, and LC3 on the Anaplasma inclusion. This induces the membrane vesicle formation. Ats-1 by itself can nucleate autophagosomes decorated around Anaplasma inclusions with ER autophagy proteins. Ats-1 promotes the growth of Anaplasma phagocytophilum in host cells. Depleting beclin suppresses parasite infection [PMID23197835]- [PMID23388398].

Deficient in intracellular replication A: F. tularensis mutants in which the gene for DipA is disabled are targeted, in murine and human macrophages, to autophagic vacuoles unlike wild-type bacteria. DipA is required for cytosolic replication but not phagosomal escape. Macrophage vacuoles containing replication-deficient bacteria were labeled with ubiquitin and the autophagy receptors SQSTM1/p62 and NBR1, and their formation was decreased in macrophages from either ATG5-, LC3B- or SQSTM1-deficient mice, indicating recognition by the ubiquitin-SQSTM1-LC3 pathway [PMID22863802].

BopA is an effector injected into host cells via a type III secretion system. It prevents targeting of the B. pseudomallei bacterium via LC3-associated phagocytosis, a form of xenophagy [PMID22790007].

Escherichia coli secreted protein G (EspG): Both EspG and EspG2 function as GTPase activating proteins for Rab1 to inhibit autophagy and vesicular traffic from the ER to the Golgi [PMID22425230].

CbpC of Streptococcus pneumoniae dampens autophagy by promoting the degradation of host ATG14 (UniprotQ6ZNE5) through its interaction with sequestosome1 [PMID32508214].

CvpB/Cig2 is a T4SS effector important for interactions between the Coxiella-containing vacuole and host autophagosomes and this enhances the fusogenic properties of the CCV. The CCV has a unique ability to fuse promiscuously with other host compartments of the C. burnetii-infected cell. This requires a functional host autophagic system [PMID25080348].

Etf-1 is a T4aSS effector that localizes to ehrlichial inclusions and binds Rab5 and the autophagy-initiating class III PtdIns-3-kinase complex. Ectopically expressed Etf-1 activates class III PtdIns-3 kinase and induces autophagosome formation. It also enhances proliferation of Ehrlichia. The bacteria manipulates host autophagy for its own nutritional needs [PMID27541856].

I've got a couple dozen more for bacteria and maybe 10 for viruses, but that's a taste. Also, I would eventually like to be able to specify exactly which host proteins could be manipulated so it would be obvious which parasite proteins are messing with it, but a lot of papers don't investigate that deeply--they are looking at autophagic vesicle formation and aren't looking at what is going on at the molecular level so you have a certain level of cell biological phenomenology. I don't want to discount those observations, though.

[genegodbold]

Also @jproesch, I might be thinking of phagocytosis differently than most people (I don't know). When the people I'm reading investigate phagocytosis, they are concerned with uptake of foreign material. So interfering with uptake by influencing the molecular dynamics of the cytoskeleton or the membrane, or phagocytic receptors is sufficient to qualify as interrupting phagocytosis.

So notice that what happens to the cellular material AFTER that, doesn't enter into the disruption of phagocytosis. Of course, PathGO makes this same distinction--you have a bunch of terms that deal with what happens to the material AFTER it gets in the cell. Does it get interrupted on the way to the phagosome? The lysosome? So you see that you have a distinction based on "uptake" and "delivery" already in the ontology. Xenophagy/autophagy use the same set of host proteins (beclin, autophagy receptors, some vesicle markers) but involve an alternate pathway for the final disposal of the material that has been taken up. I think it is important to note when these host pathways are inhibited/suppressed by the parasite.

I was in grad school in the first half of the 1990s and my advisor told me (back then) that half of what we knew about eukaryotic cell biology had been revealed to us by studying viral infections of cells (and she had been a postdoc in Gunter Blobel's lab). I might quibble with her estimate a little, but parasites have certainly been the catalyst for understanding an awful lot of how our own cells work.

[jproesch]

@genegodbold thanks! I was seeing things out there where some folks were using phagocytosis and xenophagy synonymously, but I am also seeing the nuance I think you are pointing out...that phagocytosis is uptake into the cell, while xenophagy/autophagy happens after. Given we have some related terms concerning what happens after under endomembrane system, I'm thinking this might also fit there.

[genegodbold]

@jproesch Yes, my only point is that we need a term that recognizes that these specific host processes are being manipulated by the parasite. None of the others are synonymous. So just to be clear, I don't think the other membrane terms OR the delivery terms capture what needs to be noted by having a modulation of autophagy term.