ABSTRACT
Optimal activation of stimulator of interferon genes (STING) protein is crucial for host defenses against pathogens and avoiding detrimental effects. Various post-translational modifications control STING activity. However, the function of interferon (IFN)-stimulated gene (ISG) 15 modification (ISGylation) in controlling STING stability and activation is unclear. Here, we show that the E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation. Concordantly, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo. Notably, severe acute respiratory syndrome coronavirus 2 protein papain-like protease cleaves HERC5-mediated ISGylation of STING, suppressing host antiviral responses. These data identify a mechanism by which HERCs-mediated ISGylation controls STING stability and activation and uncover the correlations and interactions of ISGylation and ubiquitination during STING activation.
Subject(s)
Membrane Proteins , Ubiquitin-Protein Ligases , Ubiquitination , Ubiquitins , Animals , Humans , Mice , Cytokines/metabolism , HEK293 Cells , Herpes Simplex/virology , Herpes Simplex/metabolism , Herpes Simplex/immunology , Herpesvirus 1, Human/physiology , Interferon Type I/metabolism , Intracellular Signaling Peptides and Proteins , Membrane Proteins/metabolism , Mice, Inbred C57BL , SARS-CoV-2/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitins/metabolism , Virus Replication , Male , FemaleABSTRACT
Compounded aluminum hydroxide (ATH) flame retardants have been widely used for their low cost and environmentally friendly characteristics. However, previous research lacks a systematic and comprehensive comparison. In addition, the combustion characteristics and phase characterization of asphalt binders are not taken into account either. In this work, flame retardants, for instance, APP, Sb2O3, ZB, and LDHs, were compounded with ATH. The flame retardant behavior, together with the smoke suppression behavior, of asphalt binders with compounded flame retardants was determined by LOI and CCT. Furthermore, mechanisms on flame retardants were investigated. It was found that ATH compounded with ZB significantly reduced the heat smoke release and suppressed the formation of toxic volatiles during asphalt combustion. This was because ATH/ZB facilitated the formation of polyaromatic structures and improved the resistance of the char layer. ATH compounded with APP showed an antagonistic effect in the limiting oxygen test because the reaction between ATH and APP inhibited and delayed the decomposition of ATH during asphalt combustion with more aluminum phosphate presenting relatively poor barrier properties produced.
