YAP inhibits HCMV replication by impairing STING-mediated nuclear transport of the viral genome.

YES-associated protein (YAP), a critical actor of the mammalian Hippo signaling pathway involved in diverse biological events, has gained increased recognition as a cellular factor regulated by viral infections, but very few studies have investigated their relationship vice versa. In this study, we show that YAP impairs HCMV replication as assessed by viral gene expression analysis and progeny assays, and that this inhibition occurs at the immediate-early stages of the viral life cycle, at the latest. Using YAP mutants lacking key functional domains and shRNA against TEAD, we show that the inhibitory effects of YAP on HCMV replication are nuclear localization- and TEAD cofactor-dependent. Quantitative real-time PCR (qPCR) and subcellular fractionation analyses reveal that YAP does not interfere with the viral entry process but inhibits transport of the HCMV genome into the nucleus. Most importantly, we show that the expression of stimulator of interferon genes (STING), recently identified as an important component for nuclear delivery of the herpesvirus genome, is severely downregulated by YAP at the level of gene transcription. The functional importance of STING is further confirmed by the observation that STING expression restores YAP-attenuated nuclear transport of the HCMV genome, viral gene expression, and progeny virus production. We also show that HCMV-upregulated YAP reduces expression of STING. Taken together, these findings indicate that YAP possesses both direct and indirect regulatory roles in HCMV replication at different infection stages.

Identification of genetic variants for blood insulin level in sex-stratified Korean population and evaluation of the causal relationship between blood insulin level and polycystic ovary syndrome.

BACKGROUND: Blood insulin level is an important risk factor for numerous disorders. Individual blood insulin level is known to be substantially influenced by genetic factors. Several genetic association studies identified a number of genetic variants for blood insulin level, but none of them was from a sex-stratified population. OBJECTIVE: This study aimed to identify male- and female-specific genetic variants related to blood insulin level and to evaluate the causal relationship between blood insulin level and polycystic ovary syndrome (PCOS) that is likely caused by high insulin in Korean women. METHODS: A genome-wide association study was conducted to identify genetic variants influencing blood insulin level in males (N = 4183) and females (N = 4659) in the Korean population. Two-sample Mendelian randomization (MR) analysis was used to investigate the causal effects of the insulin variants identified from GWAS on PCOS in Korean women. Genetic association data for PCOS were obtained from a PCOS study cohort (946 cases, 976 controls) in Ewha Womans University Hospital. RESULTS: GWAS linear regression analysis identified 13 female-specific SNPs and 13 male-specific SNPs showing suggestive associations (P < 10-5) with blood insulin level. The results from two-sample MR analysis using the GWAS variants for PCOS indicated that genetically determined insulin level was not associated with the risk of PCOS in Korean women. CONCLUSION: This study identified sex-specific genetic variants showing associations with insulin for the first time in East Asian populations. In addition, MR analysis using variants discovered from Korean women revealed that genetically determined high level of insulin is not the cause of PCOS.