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Summary: Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV-1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.

Major histocompatibility complex I (MHC‐I) molecules present epitopes on the cellular surface of antigen‐presenting cells to prime cytotoxic clusters of differentiation 8 (CD8)+ T cells (CTLs), which then identify and eliminate other cells such as virus‐infected cells bearing the antigen. Human hepatitis virus cohort studies have previously identified MHC‐I molecules as promising predictors of viral clearance. However, the underlying functional significance of these predictions is not fully understood. Here, we show that expression of single MHC‐I isomers promotes virus‐induced liver immunopathology. Specifically, using the lymphocytic choriomeningitis virus (LCMV) model system, we found MHC‐I proteins to be highly up‐regulated during infection. Deletion of one of the two MHC‐I isomers histocompatibility antigen 2 (H2)–Db or H2‐Kb in C57Bl/6 mice resulted in CTL activation recognizing the remaining MHC‐I with LCMV epitopes in increased paucity. This increased CTL response resulted in hepatocyte death, increased caspase activation, and severe metabolic changes in liver tissue following infection with LCMV. Moreover, depletion of CTLs abolished LCMV‐induced pathology in these mice with resulting viral persistence. In turn, natural killer (NK) cell depletion further increased antiviral CTL immunity and clearance of LCMV even in the presence of a single MHC‐I isomer. Conclusion: Our results suggest that uniform MHC‐I molecule expression promotes enhanced CTL immunity during viral infection and contributes to increased CTL‐mediated liver cell damage that was alleviated by CD8 or NK cell depletion.

Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interest for the design of ATP-competitive inhibitors of human CK2. In the present study, we prepared twenty-one indeno[1,2-b]indole derivatives, all of which were tested in vitro on human CK2. The indenoindolones 5a and 5b inhibited human CK2 with an IC50 of 0.17 and 0.61 µM, respectively. The indeno[1,2-b]indoloquinone 7a also showed inhibitory activity on CK2 at a submicromolar range (IC50 = 0.43 µM). Additionally, a large number of indenoindole derivatives was evaluated for their cytotoxic activities against the cell lines 3T3, WI-38, HEK293T and MEF.