Alterations in global mRNA decay broadly impact multiple stages of gene expression, although signals that connect these processes are incompletely defined. Here, we used tandem mass tag labeling coupled with mass spectrometry to reveal that changing the mRNA decay landscape, as frequently occurs during viral infection, results in subcellular redistribution of RNA binding proteins (RBPs) in human cells. Accelerating Xrn1-dependent mRNA decay through expression of a gammaherpesviral endonuclease drove nuclear translocation of many RBPs, including poly(A) tail-associated proteins. Conversely, cells lacking Xrn1 exhibited changes in the localization or abundance of numerous factors linked to mRNA turnover. Using these data, we uncovered a new role for relocalized cytoplasmic poly(A) binding protein in repressing recruitment of TATA binding protein and RNA polymerase II to promoters. Collectively, our results show that changes in cytoplasmic mRNA decay can directly impact protein localization, providing a mechanism to connect seemingly distal stages of gene expression.

Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host–pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host–pathogen interactions that represent anti‐ and pro‐pathogenic cellular responses. Here, we review these proteomic methods and their application to studying viral and bacterial intracellular pathogens. We examine approaches for defining spatial and temporal host–pathogen protein interactions upon infection of a host cell. Further expanding the understanding of proteome organization during an infection, we discuss methods that characterize the regulation of host and pathogen proteomes through alterations in protein abundance, localization, and post‐translational modifications. Finally, we highlight bioinformatic tools available for analyzing such proteomic datasets, as well as novel strategies for integrating proteomics with other omic tools, such as genomics, transcriptomics, and metabolomics, to obtain a systems‐level understanding of infectious diseases.

Purpose: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA) 5/6/7 repeat polymorphism in UGT1A1 Ã 28 (UGT, uridine glucuronosyl transferase Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1 Ã 28 alleles (n ¼ 12 and n ¼ 5; R 2 ¼ 0.38 and R 2 ¼ 0.77; P ¼ 0.032 and P ¼ 0.051, respectively). UGT1A1 Ã 28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure.Conclusions: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.

Article Interactome and Proteome Dynamics Uncover Immune Modulatory Associations of the Pathogen Sensing Factor cGAS Graphical Abstract Highlights d Defined global network of cytoplasmic cGAS protein interactions upon HSV-1 infection d Mapped the temporal proteomes with IFN-and apoptosisinducing HSV-1 strains d Oligoadenylate synthase-like domain of OASL associates with cGAS in the cytoplasm d OASL negatively regulates cGAS-mediated cytokine induction SUMMARY Viral DNA sensing is an essential component of the mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection.Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus type 1 (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry. Follow-up analyses establish a functional interaction between cGAS and 2ʹ-5ʹ-oligoadenylate synthase-like protein OASL. The OAS-like domain interacts with the cGAS Mab21 domain, while the OASL ubiquitin-like domain further inhibits cGASmediated interferon response. Our findings explain how cGAS may be inactively maintained in cellular homeostasis, with OASL functioning as a negative feedback loop for cytokine induction.

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