title: Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication.
abstract: Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and HCMV infection in immunocompromised patients may trigger devastating disease. Cytotoxic lymphocytes control HCMV by releasing granzymes towards virus-infected cells. In mice, granzyme M (GrM) has a physiological role in controlling murine CMV infection. However, the underlying mechanism remains poorly understood. In this study, we showed that human GrM was expressed by HCMV-specific CD8(+) T cells both in latently infected healthy individuals and in transplant patients during primary HCMV infection. We identified host cell heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a physiological GrM substrate. GrM most efficiently cleaved hnRNP K in the presence of RNA at multiple sites, thereby likely destroying hnRNP K function. Host cell hnRNP K was essential for HCMV replication not only by promoting viability of HCMV-infected cells but predominantly by regulating viral immediate-early 2 (IE2) protein levels. Furthermore, hnRNP K interacted with IE2 mRNA. Finally, GrM decreased IE2 protein expression in HCMV-infected cells. Our data suggest that targeting of hnRNP K by GrM contributes to the mechanism by which cytotoxic lymphocytes inhibit HCMV replication. This is the first evidence that cytotoxic lymphocytes target host cell proteins to control HCMV infections.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Domselaar
authors.forename: S A H
authors.initials: SA
authors.lastname: de Poot
authors.forename: E B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.forename: K W
authors.initials: KW
authors.lastname: Lai
authors.forename: I J M
authors.initials: IJ
authors.lastname: ten Berge
authors.forename: N
authors.initials: N
authors.lastname: Bovenschen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000821:virology; D053804:Granzymes / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D016296:Mutagenesis; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D034641:Heterogeneous-Nuclear Ribonucleoprotein K; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; D012313:RNA; D053804:Granzymes