In the tongue, distinct classes of taste receptor cells detect the five basic tastes, sweet, sour, bitter, sodium salt, and umami1,2. Among these qualities, bitter and sour stimuli are innately aversive, whereas sweet and umami are appetitive, and generally attractive to animals. In contrast, salty taste is unique in that increasing salt concentration fundamentally transforms an innately appetitive stimulus into a powerfully aversive one3–7. This appetitive-aversive balance helps maintain appropriate salt consumption3,4,6,8, and represents an important part of fluid and electrolyte homeostasis. We have previously shown that the appetitive responses to NaCl are mediated by taste receptor cells expressing the epithelial sodium channel, ENaC8, while the cellular substrate for salt aversion was unknown. Here we explore the cellular and molecular basis for the rejection of high concentrations of salts (>300 mM NaCl or KCl). We now show that high-salt recruits the two primary aversive taste pathways by activating the sour and bitter taste-sensing cells. We also demonstrate that genetic silencing of these pathways abolishes behavioral aversion to concentrated salt, without impairing salt attraction. Notably, mice devoid of salt-aversion pathways now exhibit unimpeded, continuous attraction even to exceedingly high concentrations of NaCl. We propose that the “co-opting” of sour and bitter neural pathways evolved as a means to ensure that high levels of salt reliably trigger robust behavioral rejection, thus preventing its potentially detrimental effects in health and well-being.

Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi’s sarcoma and other aggressive AIDS-associated malignancies, encodes over 90 genes, most of which are expressed only during the lytic replication cycle. The role of many of the KSHV lytic proteins in the KSHV replication cycle remains unknown, and many proteins are annotated based on known functions of homologs in other herpesviruses. Here we investigate the role of the previously uncharacterized KSHV lytic protein ORF42, a presumed tegument protein. We find that ORF42 is dispensable for reactivation from latency but is required for efficient production of viral particles. Like its alpha- and beta-herpesviral homologs, ORF42 is a late protein that accumulates in the viral particles. However, unlike its homologs, ORF42 appears to be required for efficient expression of at least some viral proteins and may potentiate post-transcriptional stages of gene expression. These results demonstrate that ORF42 has an important role in KSHV replication and may contribute to shaping viral gene expression.

Purpose of review Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiological agent of the AIDS-associated tumor Kaposi’s sarcoma, is a complex virus that expresses ~90 proteins in a regulated temporal cascade during its replication cycle. Although KSHV relies on cellular machinery for gene expression, it also uses specialized regulators to control nearly every step of the process. In this review we discuss the current understanding of KSHV gene regulation. Recent findings High-throughput sequencing and a new robust system to mutate KSHV have paved the way for comprehensive studies of KSHV gene expression, leading to the characterization of new viral factors that control late gene expression and post-transcriptional steps of gene regulation. They have also revealed key aspects of chromatin-based control of gene expression in the latent and lytic cycle. Summary The combination of mutant analysis and high-throughput sequencing will continue to expand our model of KSHV gene regulation and point to potential new targets for anti-KSHV drugs.

17The tight control of viral and host gene expression is critical to the replication of herpesviruses, 18 including the gamma-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV). While 19 some of the KSHV proteins that contribute to viral and host gene regulation are known, it is clear 20 that there are additional uncharacterized contributing viral factors. Identifying these proteins and 21 their role in gene regulation is important to determine the mechanistic underpinnings of the 22 complex replication cycle of KSHV. Through a reporter-based screen, we have identified several 23 new potential KSHV-encoded gene regulators, including the previously uncharacterized protein 24 ORF42, which we find stimulates global protein production upon overexpression. We have 25 generated an ORF42-null virus, which revealed that ORF42 is required for wild-type levels of 26 virus production. Moreover, global protein synthesis and the accumulation of viral proteins are 27 reduced in infected cells in the absence of ORF42, suggesting that ORF42 regulates protein 28 synthesis during infection. A comparison of the effects of ORF42 on the levels of RNA and 29 protein suggests that ORF42 acts post-transcriptionally to control protein levels. In addition to 30 gene regulation, ORF42 may have other functions in virion formation, as it is found in viral 31 particles, which is consistent with the described roles of the ORF42 homologs in alpha-and beta-32 herpesviruses. 33 3 Importance 34 Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, an AIDS-associated 35 malignancy that remains one of the leading causes of cancer deaths in sub-Saharan Africa. 36 Replication of the virus is important for tumor formation and inhibition of viral replication may 37 be used for treatment. The correct levels and temporal expression of viral and host genes during 38 KSHV replication are key to viral replication, but the mechanisms that control this regulation 39 remain enigmatic. Here we identify several new KSHV proteins involved in viral and cellular 40 gene regulation and characterize the previously unstudied KSHV ORF42 protein in regulation of 41 viral and host protein levels and efficient formation of viral progeny. 42 4 Introduction 43