Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal human fibroblast line, TIG-3 which senesces at around 80 population doubling levels (PDLs), expressed interferon (IFN)-inducible genes such as 6-16, 2', 5'-oligoadenylate synthetase (2,5-A) and HLA B7 near the end of the proliferative lifespan. Other normal fibroblast line such as MRC-5 also expressed IFN-inducible genes when senesced. Clones transformed with SV40 T-antigen, which extended their proliferative lifespan by about 20-30 PDLs, also expressed IFN-inducible genes during their extended life. Anti-IFN-beta antibodies added in culture medium repressed the expression of IFN-inducible gene in both normal senescent and life-extended SV40-transformed cells. IFN-beta repressed DNA synthesis in normal TIG-3 and induced IFN-inducible genes in both normal and SV40-transformed TIG-3. Conditioned medium recovered from life-extended SV40-transformed cells contained IFN-beta, but not IFN-alpha, IFN-gamma or TNF-alpha and possessed an activity that inhibited DNA synthesis of young TIG-3. Addition of anti-IFN-beta antibodies into the medium enhanced the serum-induced DNA synthesis of near senescent (91% lifespan completed) TIG-3, while it neither induced DNA synthesis in fully senescent TIG-3 nor extended the proliferative lifespan of TIG-3. These results suggest that normal and SV40-transformed human fibroblasts increase expression of IFN-beta with increasing proliferative age especially near the end of their lifespan resulting in induction of IFN-inducible genes and possibly in growth repression.
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PMID:Increase in expression levels of interferon-inducible genes in senescent human diploid fibroblasts and in SV40-transformed human fibroblasts with extended lifespan. 756 72

Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1-positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.
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PMID:Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. 1739 80

Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune diseases. In contrast, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the redistribution have not been fully elucidated. Ras related in brain (Rab)7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation. In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-alpha, IL-6, and IFN-beta in macrophages by impairing activation of MAPKs and NF-kappaB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
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PMID:Late endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and type I IFN production in macrophages. 1958 7

RNA virus infection is recognized by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) in the cytoplasm. RLRs are comprised of N-terminal caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain. The third member of the RLR family, LGP2, lacks any CARDs and was originally identified as a negative regulator of RLR signaling. In the present study, we generated mice lacking LGP2 and found that LGP2 was required for RIG-I- and MDA5-mediated antiviral responses. In particular, LGP2 was essential for type I IFN production in response to picornaviridae infection. Overexpression of the CARDs from RIG-I and MDA5 in Lgp2(-/-) fibroblasts activated the IFN-beta promoter, suggesting that LGP2 acts upstream of RIG-I and MDA5. We further examined the role of the LGP2 helicase domain by generating mice harboring a point mutation of Lys-30 to Ala (Lgp2 (K30A/K30A)) that abrogated the LGP2 ATPase activity. Lgp2 (K30A/K30A) dendritic cells showed impaired IFN-beta productions in response to various RNA viruses to extents similar to those of Lgp2(-/-) cells. Lgp2(-/-) and Lgp2 (K30A/K30A) mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands for MDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.
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PMID:LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. 2013 87