Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ. In hematopoietic cells and in resident brain cells, USP15 was coexpressed with, and functionally acted together with the E3 ubiquitin ligase TRIM25 to positively regulate type I interferon responses and to promote pathogenesis during neuroinflammation. The USP15-TRIM25 dyad might be a potential target for intervention in acute or chronic states of neuroinflammation.
Kennedy et al. identify a mutation in coiled-coil domain containing protein 88b (Ccdc88b) that confers protection against lethal neuroinflammation during experimental cerebral malaria. CCDC88B is expressed in immune cells and regulates T cell maturation and effector functions. In humans, the CCDC88B gene maps to a locus associated with susceptibility to several inflammatory and autoimmune disorders.
The E2 protein of human papillomavirus (HPV) binds to specific sites in the viral genome to regulate its transcription, replication, and maintenance in infected cells. Like most regulatory proteins, E2 is rapidly turned over. A high-throughput assay was developed to quantify the expression and stability of E2 in vivo, based on its fusion to Renilla luciferase (RLuc). The steady-state levels of Rluc-E2 were quantified by measuring the amounts of associated luciferase activity, and its degradation was measured by monitoring the decrease in enzymatic activity occurring after a block of translation with cycloheximide. Using this assay, the E2 proteins from a low-risk (HPV11) and a high-risk (HPV31) human papillomavirus (HPV) type were found to have short half-lives of 60 min in C33A cervical carcinoma cells and to be ubiquitinated and degraded by the proteasome. Analysis of mutant proteins showed that the instability of E2 is independent of its DNAbinding and transcriptional activities but is encoded within its transactivation domain, the region that binds to the cellular chromatin factor bromodomain-containing protein 4 (Brd4) to regulate viral gene transcription. Overexpression of Brd4, or of its C-terminal E2-interaction domain, was found to increase the steady-state levels and stability of wild-type E2 but not of E2 mutants defective for binding Brd4. These results indicate that the stability of E2 is increased upon complex formation with Brd4 and highlight the value of the luciferase assay for the study of E2 degradation.Papillomaviruses are a family of small double-stranded DNA viruses that induce benign and malignant hyperproliferative lesions of the differentiating epithelium (24,25,49). Approximately 25 types of human papillomavirus (HPV) infect the anogenital region. The oncogenic or "high-risk" types, such as HPV16, -18, and -31, are found in the majority of cervical and anal cancers and their precursor lesions (7,25,49). They are also present in a subset of head-and-neck cancers (22, 42). The low-risk types, including HPV6 and -11, cause benign genital warts (condylomas) (29) and laryngeal papillomatosis (6), a rare but debilitating infection acquired by infants during birth from an infected mother.The life cycle of HPV is coupled to the cellular differentiation program that keratinocytes undergo in the epithelium (17,25,32). These viruses infect the basal cell layer, where they maintain their double-stranded DNA genome as a circular episome in the nucleus of infected cells. Maintenance of the HPV episome in primary keratinocyte cultures requires four viral proteins: the two oncogenes, E6 and E7, the E1 replicative helicase, and the multifunctional E2 protein (25, 32). E2 binds to specific sites in the regulatory region of the viral genome to promote its replication, regulate its transcription, and ensure its proper segregation to daughter cells at mitosis (11). E2 is comprised of two functional domains, an N-terminal transactivation domain (TAD) and a C-terminal DNA-binding/dimerization domain separated...
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