During viral infection, sensing of cytosolic DNA by the cyclic GMP-AMP synthase (cGAS) activates the adaptor protein STING and triggers an antiviral response. Little is known about the mechanisms that determine the kinetics of activation and deactivation of the cGAS-STING pathway, ensuring effective but controlled innate antiviral responses. Here we found that the ubiquitin ligase Trim38 targets cGas for sumoylation in uninfected cells and during the early phase of viral infection. Sumoylation of cGas prevented its polyubiquitination and degradation. Trim38 also sumoylated Sting during the early phase of viral infection, promoting both Sting activation and protein stability. In the late phase of infection, cGas and Sting were desumoylated by Senp2 and subsequently degraded via proteasomal and chaperone-mediated autophagy pathways, respectively. Our findings reveal an essential role for Trim38 in the innate immune response to DNA virus and provide insight into the mechanisms that ensure optimal activation and deactivation of the cGAS-STING pathway.
Conventional type 1 dendritic cells (cDC1s 1 ) are thought to perform antigen cross-presentation required to prime CD8 T cells 2 , 3 , while cDC2 are considered specialized for priming CD4 T cells 4 , 5 . CD4 T cells are also thought to help CD8 T cell responses through a variety of mechanisms 6 – 11 , including a model in which CD4 T cells ‘license’ cDC1 for CD8 T cell priming 12 . However, this model has not been directly tested in vivo or in the setting of a help-dependent tumour rejection. Here, we generated an Xcr1 -Cre mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4 and CD8 T cells. As expected, tumour rejection required cDC1, and expression of MHC-I by cDC1. Unexpectedly, early priming of CD4 T cell against tumour-derived antigens also required cDC1, which was not simply due to a role in antigen transport to lymph nodes for processing by cDC2, since selective deletion of MHC-II in cDC1 also prevented early CD4 T cell priming. Further, deletion of either MHC-II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4 T cell interactions and CD40 signaling in cDC1 licensing. Finally, CD40 signaling in cDC1 was critical not only for CD8 T cell priming, but also for initial CD4 T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4 and CD8 T cells and directly orchestrating their cross-talk required for optimal anti-tumour immunity.
The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.
We describe a scheme for time integration of mass-spring systems that makes use of a solver based on block coordinate descent. This scheme provides a fast solution for classical linear (Hookean) springs. We express the widely used implicit Euler method as an energy minimization problem and introduce spring directions as auxiliary unknown variables. The system is globally linear in the node positions, and the non-linear terms involving the directions are strictly local. Because the global linear system does not depend on run-time state, the matrix can be pre-factored, allowing for very fast iterations. Our method converges to the same final result as would be obtained by solving the standard form of implicit Euler using Newton's method. Although the asymptotic convergence of Newton's method is faster than ours, the initial ratio of work to error reduction with our method is much faster than Newton's. For real-time visual applications, where speed and stability are more important than precision, we obtain visually acceptable results at a total cost per timestep that is only a fraction of that required for a single Newton iteration. When higher accuracy is required, our algorithm can be used to compute a good starting point for subsequent Newton's iteration. AbstractWe describe a scheme for time integration of mass-spring systems that makes use of a solver based on block coordinate descent. This scheme provides a fast solution for classical linear (Hookean) springs. We express the widely used implicit Euler method as an energy minimization problem and introduce spring directions as auxiliary unknown variables. The system is globally linear in the node positions, and the non-linear terms involving the directions are strictly local. Because the global linear system does not depend on run-time state, the matrix can be pre-factored, allowing for very fast iterations. Our method converges to the same final result as would be obtained by solving the standard form of implicit Euler using Newton's method. Although the asymptotic convergence of Newton's method is faster than ours, the initial ratio of work to error reduction with our method is much faster than Newton's. For real-time visual applications, where speed and stability are more important than precision, we obtain visually acceptable results at a total cost per timestep that is only a fraction of that required for a single Newton iteration. When higher accuracy is required, our algorithm can be used to compute a good starting point for subsequent Newton's iteration.
Composition engineering is a particularly simple and effective approach especially using mixed cations and halide anions to optimize the morphology, crystallinity, and light absorption of perovskite films. However, there are very few reports on the use of anion substitutions to develop uniform and highly crystalline perovskite films with large grain size and reduced defects. Here, the first report of employing tetrafluoroborate (BF 4 − ) anion substitutions to improve the properties of (FA = formamidinium, MA = methylammonium (FAPbI 3 ) 0.83 (MAPbBr 3 ) 0.17 ) perovskite films is demonstrated. The BF 4 − can be successfully incorporated into a mixed-ion perovskite crystal frame, leading to lattice relaxation and a longer photoluminescence lifetime, higher recombination resistance, and 1-2 orders magnitude lower trap density in prepared perovskite films and derived solar cells. These advantages benefit the performance of perovskite solar cells (PVSCs), resulting in an improved power conversion efficiency (PCE) of 20.16% from 17.55% due to enhanced open-circuit voltage (V OC ) and fill factor. This is the highest PCE for BF 4 − anion substituted lead halide PVSCs reported to date. This work provides insight for further exploration of anion substitutions in perovskites to enhance the performance of PVSCs and other optoelectronic devices.
Viral infection activates transcription factors, such as NF-κB and IFN regulatory factor 3, which collaborate to induce type I IFNs and elicit innate antiviral response. Virus-induced signaling adaptor (VISA) has been identified as a critical adaptor required for virus-triggered induction of type I IFNs. In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase. These findings suggest that RNF5-mediated ubiquitination and degradation of VISA is one of the mechanisms of the regulation of virus-triggered induction of type I IFNs and cellular antiviral response.
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