Convergent perturbation of the human domain-resolved interactome by viruses and mutations inducing similar disease phenotypes

Abstract

An important goal of systems medicine is to study disease in the context of genetic and environmental perturbations to the human interactome network. For diseases with both genetic and infectious contributors, a key postulate is that similar perturbations of the human interactome by either disease mutations or pathogens can have similar disease consequences. This postulate has so far only been tested for a few viral species at the level of whole proteins. Here, we expand the scope of viral species examined, and test this postulate more rigorously at the higher resolution of protein domains. Focusing on diseases with both genetic and viral contributors, we found significant convergent perturbation of the human domain-resolved interactome by endogenous genetic mutations and exogenous viral proteins inducing similar disease phenotypes. Pan-cancer, pan-oncovirus analysis further revealed that domains of human oncoproteins either physically targeted or structurally mimicked by oncoviruses are enriched for cancer driver rather than passenger mutations, suggesting convergent targeting of cancer driver pathways by diverse oncoviruses. Our study provides a framework for high-resolution, network-based comparison of various disease factors, both genetic and environmental, in terms of their impacts on the human interactome.

Fig 1. Virus-targeted host proteins tend to be causally associated with virally-implicated diseases (VIDs).

“VID proteins” have at least one missense variant that is causally associated with a VID, whereas all missense variants of “non-VID proteins” are exclusively associated with non-VIDs. Literature-curated, virus-specific diseases for EBV, HPV and HIV are listed in S1 Table. For pooled analysis of oncoviruses, VIDs include all types of cancer (Methods). For pooled analysis of all viruses, VIDs include all proliferative and immunological diseases (Methods). Error bars represent 95% confidence intervals.

Fig 2. Virus-targeted host domains tend to harbour mutations causally associated with virally-implicated diseases (VIDs).

“VID mutations” are causally associated with at least one VID, whereas “non-VID mutations” are exclusively associated with non-VIDs. Error bars represent 95% confidence intervals.

Fig 3. Exclusive localization or enrichment of VID mutations in virus-targeted domains.

(A) Exclusive localization of mutations causing lung cancer, an EBV-implicated disease, in EBV-targeted tyrosine kinase domain of EGFR protein. (B) Exclusive localization of mutations causing vulvar cancer and lung cancer, both HPV-implicated diseases, in HPV-targeted B domain of RB protein. (C) Exclusive localization of mutations causing cervical cancer, an HIV-implicated disease, in HIV-targeted PI3-kinase domain of MTOR protein, while mutations causing other diseases such as focal cortical dysplasia and Smith-Kingsmore syndrome are evenly distributed among all domains of MTOR. (D) Moderate enrichment of oncomutations in KSHV-targeted SH2 domain of PTPN11 protein, compared to mutations causing Noonan syndrome. Most of the oncomutations cause juvenile myelomonocytic leukemia, a disease although not caused by KSHV, is mimicked clinically and morphologically by other human herpesvirus infections, including EBV, CMV and HHV-6. VID mutations are shown as dark green diamonds. Non-VID mutations are shown as orange diamonds. Amino acid residues in virus-targeted domains are shown as light green squares. Residues in domains not targeted by virus are shown as yellow squares.

Fig 4. Viral and mutational perturbations of host domains are mechanistically similar.

(A) Viruses encode homologues of human proteins to mimic mutations in oncoproteins that cause uncontrolled cell proliferation. Top: EGFRvIII deletion mutation, frequently detected in glioblastoma multiforme (GBM) patients, and v-ErbB, encoded by avian leukosis virus, both lack the EGFR ligand-binding domain. Meanwhile, an L858R missense mutation in the EGFR kinase domain is frequently found in non-small-cell lung cancer (NSCLC). These alterations lead to conformational changes that result in ligand-independent, constitutive kinase activity [61, 62]. (B) Viruses encode homologues of human proteins to antagonize mutations in cytokine receptors that cause hypersensitivity. Human IL-10 functions both as an immunosuppressant in the inhibition of proinflammatory cytokines, and as an immunostimulant in the induction of MHC II expression on B cells. Mutations in the IL10-binding domain of IL-10R1 abrogate hIL10-induced phosphorylation, leading to loss of immunosuppression and inflammatory bowel disease [63]. In contrast, viral IL-10 homologues encoded by Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) retain and amplify the immunosuppressive properties of hIL-10, thus facilitating viral persistence after lytic infection [64]. ebvIL-10 selectively retains only the immunosuppressive properties of hIL-10. cmvIL-10 binds with greater affinity to IL-10R1 than hIL-10, while co-opting other IL10-associated pathways to amplify the immunosuppressive properties of hIL-10. Interestingly, transgenic expression of vIL-10 has been tested in animal models as an immunosuppressant option for transplant recipients [65]. In addition, abnormal expression levels of IL-10, IL10-R1 and IL10-R2 has been suggested as a mechanism for diffuse large B-cell lymphoma, a disease with clear EBV involvement [66]. (C) Viruses abuse peptide motifs to modulate host signaling pathways, potentially mimicking the effects of disease-causing mutations. Left: Kaposi’s sarcoma-associated herpesvirus (KSHV) protein K15-M uses a “PPLP” motif to bind the SH3 domain (PF00018) of Src [67], which possibly induces conformational opening of the Src kinase domain, thereby mimicking activating mutations such as Y527F [68]. Interestingly, a W121C mutation in the KSHV-targeted SH3 domain of Src has been identified in lung cancer [69]. Middle: Murine polyomavirus (MPyV) Middle T antigen (MT) uses a tyrosine-phosphorylated motif to recruit host Shc1, thereby promoting cell cycle progression [70]. Interestingly, a R175Q mutation in the MPyV-targeted PTB domain (PF00640) of Shc1 has been found to regulate tumorigenesis in mouse models of breast cancer [71]. Right: HIV protein gag uses the late-budding domain to sequester host PTPN23 and facilitate viral budding [72]. The phosphatase domain (PF00102) of PTPN23 regulates cell migration via dephosphorylation of FAK and is often mutated in cancer and developmental disorders [73, 74].

Fig 5. Oncovirus-targeted proteins are enriched for driver proteins, and oncovirus-targeted or mimicked domains are enriched for driver mutations.

(A) There is a 3-fold enrichment of Cancer Gene Census proteins in oncovirus-targeted proteins. (B) There are 5-fold and 3-fold enrichments of driver mutations in oncovirus-targeted domains (OVTDs) and oncoviral homology domains (OVHDs), respectively.

Fig 6. Oncoproteins having at least one oncovirus-targeted domain (OVTD), where driver mutations are either exclusively found or enriched.

(A) driver:passenger ratio in oncovirus-targeted PF00605 domain of IRF1 is higher than the mean driver:passenger ratio for all oncoproteins; (B) driver mutations are exclusively found in oncovirus-targeted PF07714 domain of PDGFRA; (C) driver mutations are enriched in oncovirus-targeted PF00104 domain of AR.

Fig 7. Oncoproteins having no oncovirus-targeted domain (OVTD) but at least one oncoviral homology domain (OVHD), where driver mutations are either exclusively found or enriched.

(A) driver:passenger ratio in oncovirus-mimicked PF00178 and PF02198 domains of ETV6 is higher than the mean driver:passenger ratio for all oncoproteins; (B) driver mutations are exclusively found in oncovirus-mimicked PF07714 domain of MET; (C) driver mutations are enriched in oncovirus-mimicked PF07714 domain of FGFR2.

Fig 8. Viral proteins and VID mutations perturb the same domain-domain interactions in the human interactome.

(A) From left to right, domains are cross-classified as: interacting with a domain harbouring at least one VID mutation (VDDiD) and targeted by virus, VDDiD not targeted by virus, interacting with a domain harbouring only non-VID mutations (nVDDiD) and targeted by virus, and nVDDiD not targeted by virus. (B) Viruses tend to target VDDiDs rather than nVDDiDs, regardless of whether the VDDiDs and nVDDiDs are susceptible to known disease mutations. The results for EBV and HPV are not statistically significant, possibly due to small sample sizes.

Fig 9. Viral proteins and VID mutations convergently perturb dense regions of the human domain interactome.

Examples are given for EBV (left) and HIV (right).