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Summary: Post-translational modification of ribosomal subunit proteins (RPs) is emerging as an important means of regulating gene expression. Recently, regulatory ubiquitination of small RPs RPS10 and RPS20 by the ubiquitin ligase ZNF598 was found to function in ribosome sensing and stalling on internally polyadenylated mRNAs during ribosome quality control (RQC). Here, we reveal that ZNF598 and RPS10 negatively regulate interferon-stimulated gene (ISG) expression in primary cells, depletion of which induced ISG expression and a broad antiviral state. However, cell lines lacking interferon responses revealed that ZNF598 E3 ligase activity and ubiquitination of RPS20, but not RPS10, were specifically required for poxvirus replication and synthesis of poxvirus proteins whose encoding mRNAs contain unusual 5′ poly(A) leaders. Our findings reveal distinct functions for ZNF598 and its downstream RPS targets, one that negatively regulates ISG expression and infection by a range of viruses while the other is positively exploited by poxviruses. : In addition to repressing poly(A) readthrough during ribosome quality control, DiGiuseppe et al. report that ZNF598 and RPS10 negatively regulate interferon-stimulated gene expression (ISG). However, in cell lines lacking ISG responses, ZNF598 ubiquitin ligase activity and RPS20 ubiquitination are specifically required by poxviruses, which produce unusual mRNAs with 5′ poly(A) leaders. Keywords: ZNF598, ubiquitination, ribosome, RPS, post-translational modification, specialization, translation, virus, poxvirus

Summary: End-binding proteins (EBs) are widely viewed as master regulators of microtubule dynamics and function. Here, we show that while EB1 mediates the dynamic microtubule capture of herpes simplex virus type 1 (HSV-1) in fibroblasts, in neuronal cells, infection occurs independently of EBs through stable microtubules. Prompted by this, we find that transforming acid coiled-coil protein 3 (TACC3), widely studied in mitotic spindle formation, regulates the cytoplasmic localization of the microtubule polymerizing factor chTOG and influences microtubule plus-end dynamics during interphase to control infection in distinct cell types. Furthermore, perturbing TACC3 function in neuronal cells resulted in the formation of disorganized stable, detyrosinated microtubule networks and changes in cellular morphology, as well as impaired trafficking of both HSV-1 and transferrin. These trafficking defects in TACC3-depleted cells were reversed by the depletion of kinesin-1 heavy chains. As such, TACC3 is a critical regulator of interphase microtubule dynamics and stability that influences kinesin-1-based cargo trafficking. : While EB proteins are widely studied as master regulators of microtubule plus-end dynamics, Furey et al. report EB-independent regulation of microtubule arrays and cargo trafficking by the transforming acid coiled-coil-containing protein, TACC3. By controlling the formation of detyrosinated stable microtubule networks, TACC3 influences kinesin-1-based sorting of both host and pathogenic cargoes. Keywords: TACC3, microtubules, +TIP, cargo transport, virus