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The molecular basis for these phenotypes remains elusive. Here we conducted a multi-proteomic survey on 64 individual VZV proteins and infection-induced perturbations in a neuronal cell line, identifying 900 interactors and 3,618 regulated host proteins. Data integration suggested molecular functions of viral proteins, such as a mechanism for the ORF61-mediated IFI16 degradation via the recruitment of E3 ligase co-factors. Moreover, we identified proviral host factors (MPP8 and ZNF280D) as potential targets to limit infection. Integration of exome sequencing analysis from patients with VZV-associated central nervous system pathologies identified nephrocystin 4 as a viral restriction factor, and its S862N variant, which showed reduced activity and decreased binding to the regulatory proteins 14-3-3. Collectively, our study provides a comprehensive herpesvirus\u2013host interface resource, which aids our understanding of disease-associated molecular perturbations and data-driven identification of antiviral treatment options.<\/jats:p>","DOI":"10.1038\/s41564-025-02068-7","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:11:23Z","timestamp":1753866683000},"page":"2048-2072","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multi-proteomic profiling of the varicella-zoster virus\u2013host interface reveals host susceptibilities to severe infection"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-4400","authenticated-orcid":false,"given":"Virginie","family":"Girault","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4981-8124","authenticated-orcid":false,"given":"Alexey","family":"Stukalov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina Elena","family":"Carter-Timofte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonny","family":"Hertzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Verin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Austen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5543-4875","authenticated-orcid":false,"given":"Darya A.","family":"Haas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9991-5336","authenticated-orcid":false,"given":"Lila","family":"Oubraham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Piras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5683-1786","authenticated-orcid":false,"given":"Susanne","family":"Maidl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2292-5982","authenticated-orcid":false,"given":"Rupert","family":"\u00d6llinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6849-9659","authenticated-orcid":false,"given":"Roland","family":"Rad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-1911","authenticated-orcid":false,"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-2695","authenticated-orcid":false,"given":"Benedikt B.","family":"Kaufer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1981-0420","authenticated-orcid":false,"given":"Robert J.","family":"Lebbink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rehwinkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-9704","authenticated-orcid":false,"given":"Trine H.","family":"Mogensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-1367","authenticated-orcid":false,"given":"Andreas","family":"Pichlmair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"2068_CR1","doi-asserted-by":"publisher","first-page":"2666","DOI":"10.1017\/S0950268817001546","volume":"145","author":"K Bollaerts","year":"2017","unstructured":"Bollaerts, K. et al. 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