Regulation of papillomavirus E2 protein by posttranslational modification

Indiana University-Purdue University Indianapolis (IUPUI)Papillomaviruses (PVs) are small, double-stranded DNA viruses. Hundreds of species have evolved to replicate in mammals, birds, and reptiles. Approximately two hundred species are estimated to infect humans alone, and these human papillomaviruses (HPVs) cause diseases ranging from benign warts to anogenital and oropharyngeal cancers. While vaccination is effective at preventing the majority of these infections and their disease outcomes, there are no successful treatments for existing infections; thus, exploration of novel therapeutic targets is warranted. PVs control expression and function of their gene products through alternative splicing, alternate start codons, and post-translational modification (PTM). The viral E2 protein regulates transcription, replication, and genome maintenance in infected cells, and PTMs have been demonstrated for E2 proteins from multiple papillomavirus types. Serine phosphorylation events were reported to influence E2 stability, and our laboratory was the first to describe in vitro acetylation events with implications for E2 transcription function. Here we report confirmation of these acetylation events in vivo and additional data elucidating the role of these PTMs in viral transcription. Moreover, we present a novel phosphorylation site for bovine papillomavirus type 1 (BPV-1) E2 at tyrosine 102 (Y102). Using phospho-deficient and phospho-mimetic point mutants, we found that this site influences E2-mediated transcription and replication, and we hypothesize that phosphorylation at Y102 regulates these activities by interrupting the association of E2 with its binding partners. We also report interaction of BPV-1 E2 and HPV-31 E2 with different receptor tyrosine kinases (TKs), most notably members of the fibroblast growth factor receptor family. We hypothesize that Y102 phosphorylation by these receptors occurs early in infection to limit viral replication and gene expression. Further studies will cement the role of RTKs in PV biology and could reveal novel therapeutic strategies

Schizophrenia, recovery and the self: An introduction to the special issue on metacognition

In this special issue, work is presented linking metacognition among persons with schizophrenia with a range of psychosocial outcomes including vocational functioning, empathy, motivation, self-evaluation, and other cognitive functions. This overview will highlight how these works allow for the quantitative study of processes which underpin alterations in self-experience in schizophrenia, which in turn allows self-experience to be studied as part of a larger set of brain-based and social phenomena whose interaction influences the trajectory of one's life and illness. We explore the hypothesis that metacognitive capacity, as a node in a larger biopsychosocial network, may be accessible by psychosocial treatment and, if successfully targeted, may disrupt the processes which perpetuate disability. Limitations and directions for future research are also discussed