Amino acid repeat signatures underlying human-pathogen interactions
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Abstract
Emerging evidence suggests that amino acid homorepeats (HRs) in proteins (HRPs) contribute to protein interactability. What is the role of HRs in human-pathogen protein interactions? We find that pathogens engage physiologically important human HRPs, thereby affecting diverse host physiological processes. From the pathogen standpoint, (i) eukaryotic pathogens engage more HRPs but with host-sparse HRs, leading to disparate and discriminate interactions, (ii) prokaryotic pathogens engage less HRPs but with host-abundant non-polar HRs via host protein proxies bringing about discriminate or promiscuous interactions and (iii) viral pathogens engage more HRPs with host-abundant polar uncharged HRs affecting promiscuous interactions using host-partner HR tract mimicry. To propel further research, we introduce a resource Hi-PHI ( http://hiphi.iisertirupati.ac.in/ ) cataloging critical information about human and pathogen HRPs and HRs. We propose mechanisms to (i) repurpose drugs targeting human HRPs engaged by pathogens for treating different infections and (ii) exploit HRs and their flanks as targets for pathogen-targeted anti-infectives.
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viruses such as human herpesvirus 5 and Epstein-barr virus that infect multiple organs and organ systems
these viruses are more likely to participate in HGT with the host (along with poxviruses). Is this pattern a coincidence?
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These findings imply that high-risk human pathogens show higher number of HRPs in their proteomes and/or employ more number of pHRPs in HPIs.
Do these pathogens also have higher numbers of other interaction factors? I'm thinking of for example bacterial proteins that structurally mimic human proteins (see Elde & Malik 2009: 10.1038/nrmicro2222)
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Although more in number, epHPI-HRPs predominantly engage in solitary interactions with human proteins, bringing about one-to-one or discriminate interactions [Figure 4B-4C]. Contrarily, HRPs of prokaryotic pathogens (ppHPI-HRPs) bring about discriminate as well as one-to-few/many i.e. promiscuous interactions with human proteins [Figure 4B-4C],
Does this have to do with whether the eukaryotic pathogen is intracellular or not?
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Compared to HPI-NonHRPs and NonHPI-HRPs, removal of hHPI-HRPs tend to significantly influence the neural differentiation of human induced pluripotent stem cells (iPSC) but not cell proliferation [Figure 3E; Figure S2H]. This suggests that the hHPI-HRPs are key for neuronal differentiation.
How many of the investigated pathogens have tropism for neurons?
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including affecting global regulation across tissues.
Isn't this predicated on the distribution of the pathogen itself in the body during infection? If a virus for example interacts with a human helicase, that helicase may have distribution broadly in all tissues, but the virus may have tropism to specific cells (ex. B cells).
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Importantly, we find that hHPI-HRPs engaged by prokaryotic and viral pathogens are predominantly enriched for regulatory processes such as chromatin organization and transcription, post-transcriptional regulation [Figure 2C].
Is this different from genes that are enriched in prokaryotic or viral genomes alone? Could it be happening by chance because of the composition of the pathogen genomes themselves?
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We drew comparisons for different attributes of hHPI-HRPs with hHPI-NonHRPs and hNonHPI-HRPs spanning phenotypes, molecular networks and gene-expression.
It would be helpful here to understand more granularly which information types are needed to expand this dataset to more species.
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We assembled a comprehensive human-pathogen protein-protein interactome (HPI) comprising of 19,537 interactions between 5,295 human proteins and 3,407 pathogen proteins pertaining to a total of 286 human cellular (prokaryotic and eukaryotic) and viral pathogens spanning different taxa [Figure 1B-1C].
I know this is highlighted in figure 1, but it would be helpful at this point to have a little more clarity on where these interactions came from. Are they only from the human-pathogen protein interactions icon dataset in the "datasets analysed" panel of Figure 1a? Can you provide citations here to make it more clear where these come from and what type of interactions these include?
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