RESUMO
Data sources A search of electronic databases (EMBASE, MEDLINE, Cochrane Oral Group Trials Register and the Cochrane Central Register of Controlled Trials) along with a manual search of various Science Citation Indexed journals.Study selection Four cross-sectional studies and one case-control study were included where percentage levels of Herpes Simplex Virus Type 1 (HSV1), Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) were sampled for in both peri-implantitis affected and healthy implant sites, with the latter used as the control. Studies were excluded that investigated any other infective agent, had fewer than ten participants, was performed in vitro or involved subjects with only periodontal disease.Data extraction and synthesis Data extraction followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guideline process. Two examiners used the Newcastle Ottawa Scale to determine overall study quality while the key information was extracted and tabulated for comparison. The data was analysed using Chi-squared test and I2 test for heterogenicity with a random effects or fixed affect models applied as appropriate. Risk difference of outcomes was displayed via a forest plot with 95% confidence intervals. Funnel plots were generated to evaluate publication bias.Results All four cross-sectional studies searched for EBV, while three also looked for CMV. The case-control study included investigated for HSV1 presence only. EBV presence in peri-implantitis sites was found to be statistically significant in three of the four studies despite obvious heterogeneity. CMV presence at peri-implantitis sites was statistically significant in all relevant studies, but the data displayed notable heterogeneity so as to render it insignificant. HSV1 exhibited similar percentage frequency in both healthy and diseased implant sites.Conclusions Virus prevalence was found to be increased in patients with peri-implantitis when compared to healthy sites but this assertion must be treated with caution as the data supporting it is weak due to the limited number of studies involved and the significant inherent heterogeneity they displayed.
Assuntos
Implantes Dentários , Peri-Implantite , Estudos de Casos e Controles , Estudos Transversais , Herpesvirus Humano 4 , HumanosRESUMO
The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.
Assuntos
Lisossomos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas de Transporte/metabolismo , Núcleo Celular/metabolismo , Microscopia Crioeletrônica , Citoplasma/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Guanosina Difosfato/metabolismo , Humanos , Lisossomos/química , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Modelos Moleculares , Proteínas Monoméricas de Ligação ao GTP/química , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Conformação Proteica , Domínios Proteicos , Multimerização Proteica , Transdução de SinaisRESUMO
Membrane targeting of the BECN1-containing class III PI 3-kinase (PI3KC3) complexes is pivotal to the regulation of autophagy. The interaction of PI3KC3 complex II and its ubiquitously expressed inhibitor, Rubicon, was mapped to the first ß sheet of the BECN1 BARA domain and the UVRAG BARA2 domain by hydrogen-deuterium exchange and cryo-EM. These data suggest that the BARA ß sheet 1 unfolds to directly engage the membrane. This mechanism was confirmed using protein engineering, giant unilamellar vesicle assays, and molecular simulations. Using this mechanism, a BECN1 ß sheet-1 derived peptide activates both PI3KC3 complexes I and II, while HIV-1 Nef inhibits complex II. These data reveal how BECN1 switches on and off PI3KC3 binding to membranes. The observations explain how PI3KC3 inhibition by Rubicon, activation by autophagy-inducing BECN1 peptides, and inhibition by HIV-1 Nef are mediated by the switchable ability of the BECN1 BARA domain to partially unfold and insert into membranes.
Assuntos
Autofagia , Proteína Beclina-1/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Relacionadas à Autofagia , Proteína Beclina-1/química , Proteína Beclina-1/genética , Sítios de Ligação , Classe III de Fosfatidilinositol 3-Quinases/química , Classe III de Fosfatidilinositol 3-Quinases/genética , Microscopia Crioeletrônica , Ativação Enzimática , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Simulação de Dinâmica Molecular , Fosfatos de Fosfatidilinositol/metabolismo , Ligação Proteica , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Relação Estrutura-Atividade , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismoRESUMO
The class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) that functions in early autophagy consists of the lipid kinase VPS34, the scaffolding protein VPS15, the tumor suppressor BECN1, and the autophagy-specific subunit ATG14. The structure of the ATG14-containing PI3KC3-C1 was determined by single-particle EM, revealing a V-shaped architecture. All of the ordered domains of VPS34, VPS15, and BECN1 were mapped by MBP tagging. The dynamics of the complex were defined using hydrogen-deuterium exchange, revealing a novel 20-residue ordered region C-terminal to the VPS34 C2 domain. VPS15 organizes the complex and serves as a bridge between VPS34 and the ATG14:BECN1 subcomplex. Dynamic transitions occur in which the lipid kinase domain is ejected from the complex and VPS15 pivots at the base of the V. The N-terminus of BECN1, the target for signaling inputs, resides near the pivot point. These observations provide a framework for understanding the allosteric regulation of lipid kinase activity.