部分ESCRT亚基通过调控STING的降解调节其活性

Stimulator of interferon genes(STING),also known as MITA,ERIS,MPYS or TMEM173,is a key player in innate immunity,specifically in the typeⅠinterferon response[1-3].It is also involved in a range of non-canonical biological functions,including autophagy,cellular metabolism,translation,and DNA repair,and has implications in many diseases[4-9].After activation by its ligands,STING translocates from endoplasmic reticulum(ER),via ERGIC,Golgi apparatus and endosomes,finally to lysosomes for degradation[4-9].However,the mechanisms by which STING is delivered to lysosomes and whether this delivery process regulates STING activity remain elusive.

Structural characterization of SARS-CoV-2 dimeric ORF9b reveals potential fold-switching trigger mechanism

The constant emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants indicates the evolution and adaptation of the virus.Enhanced innate immune evasion through increased expression of viral antagonist proteins,including ORF9b,contributes to the improved transmission of the Alpha variant;hence,more attention should be paid to these viral proteins.ORF9b is an accessory protein that suppresses innate immunity via a monomer conformation by binding to Tom70.Here,we solved the dimeric structure of SARS-CoV-2 ORF9b with a long hydrophobic tunnel containing a lipid molecule that is crucial for the dimeric conformation and determined the specific lipid ligands as monoglycerides by conducting a liquid chromatography with tandem mass spectrometry analysis,suggesting an important role in the viral life cycle.Notably,a long intertwined loop accessible for host factor binding was observed in the structure.Eight phosphorylated residues in ORF9b were identified,and residues S50 and S53 were found to contribute to the stabilization of dimeric ORF9b.Additionally,we proposed a model of multifunctional ORF9b with a distinct conformation,suggesting that ORF9b is a fold-switching protein,while both lipids and phosphorylation contribute to the switching.Specifically,the ORF9b monomer interacts with Tom70 to suppress the innate immune response,whereas the ORF9b dimer binds to the membrane involving mature virion assembly.Our results provide a better understanding of the multiple functions of ORF9b.

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.