title: Utilization of host SR protein kinases and RNA-splicing machinery during viral replication.
abstract: Although the viral genome is often quite small, it encodes a broad series of proteins. The virus takes advantage of the host-RNA-processing machinery to provide the alternative splicing capability necessary for the expression of this proteomic diversity. Serine-arginine-rich (SR) proteins and the kinases that activate them are central to this alternative splicing machinery. In studies reported here, we use the HIV genome as a model. We show that HIV expression decreases overall SR protein/activity. However, we also show that HIV expression is significantly increased (20-fold) when one of the SR proteins, SRp75 is phosphorylated by SR protein kinase (SRPK)2. Thus, inhibitors of SRPK2 and perhaps of functionally related kinases, such as SRPK1, could be useful antiviral agents. Here, we develop this hypothesis and show that HIV expression down-regulates SR proteins in Flp-In293 cells, resulting in only low-level HIV expression in these cells. However, increasing SRPK2 function up-regulates HIV expression. In addition, we introduce SR protein phosphorylation inhibitor 340 (SRPIN340), which preferentially inhibits SRPK1 and SRPK2 and down-regulates SRp75. Although an isonicotinamide compound, SPRIN340 (or its derivatives) remain to be optimized for better specificity and lower cytotoxicity, we show here that SRPIN340 suppresses propagation of Sindbis virus in plaque assay and variably suppresses HIV production. Thus, we show that SRPK, a well known kinase in the cellular RNA-processing machinery, is used by at least some viruses for propagation and hence suggest that SRPIN340 or its derivatives may be useful for curbing viral diseases.
authors.affiliation: Laboratory of Gene Expression, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuhara
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.forename: Kengo
authors.initials: K
authors.lastname: Sumi
authors.forename: Takako
authors.initials: T
authors.lastname: Oshiro
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoshinaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Leonard A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D006678:HIV / Q000235:genetics; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D012845:Sindbis Virus / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: D016601:RNA-Binding Proteins