Regulation Mechnism Of Small G Protein Rif On TLR3 Ligand-Induced Host Innate Activation

The Rho subfamily of small G proteins is a ubiquitously expressed cytoplasmic protein,belonging to the small GTPase family.The small Rho GTPase acts as a molecular switch to control the activity of a series of downstream effector proteins,thereby regulating gene transcription,cell cycle progression,membrane vesicle transportation,and actin cytoskeleton.It is known that the classic family members RhoA,Rac and Cdc42 can participate in the immune responses by regulating gene expression.Whether small Rho GTPase Rif is also involved in the regulation of immune response and the development of the immune system tumor are still unclear.This study found that poly(I:C)can induce Rif activation and act through TLR3-Src-PI3K-Rif axis to induce NF-?B and IRF-3 dependent gene transcription.In addition,Rif was also revealed to enhance p38 MAPK mediated AP-1 transcription downstream of TLR3 singling pathway.Moreover,according to the cancer patient case analysis obtained from the TCGA database,the locations of Rif protein mutations in chromosomes are not concentrated in a certain area in cancer patients,indicating that Rif mutation is not a high-frequency event in cancer patients.Rif may play a role in the cancer development by modifying its expression levels.RNA-seq analysis after knocking down Rif in large B cell lymphoma cell line Karpas-422 showed that the upregulated differential genes are mainly concentrated in the signaling pathways of antigens and antibodies presentation and the immune responses,while the downregulated differential genes are mainly concentrated in Ras signaling pathway and regulation of cytoskeleton.This thesis is the first study to uncover the role of small Rho GTPase Rif in innate immune responses mediated by pattern recognition receptors under viral infection,as well as to investigate the relationship between excessive activation of Rif and tumor development in immune system.These studies reveal the novel signal transduction pathways that antagonize viral infections and deepen the understanding of the molecular mechanism of Rif in infection and pathogenicity.