Infectious diseases, such as (Mtb)-caused tuberculosis (TB), remain a global threat exacerbated by increasing drug resistance. Host-directed therapy (HDT) is a promising strategy for infection treatment through targeting host immunity. However, the limited understanding of the function and regulatory mechanism of host factors involved in immune defense against infections has impeded HDT development. Here, we identify the ubiquitin ligase (E3) TRIM27 (tripartite motif-containing 27) as a host protective factor against Mtb by enhancing host macroautophagy/autophagy flux in an E3 ligase activity-independent manner. Mechanistically, upon Mtb infection, nuclear-localized TRIM27 increases and functions as a transcription activator of (transcription factor EB). Specifically, TRIM27 binds to the promoter and the TFEB transcription factor CREB1 (cAMP responsive element binding protein 1), thus enhancing CREB1- promoter binding affinity and promoting CREB1 transcription activity toward , eventually inducing autophagy-related gene expression as well as autophagy flux activation to clear the pathogen. Furthermore, TFEB activator 1 can rescue TRIM27 deficiency-caused decreased autophagy-related gene transcription and attenuated autophagy flux, and accordingly suppressed the intracellular survival of Mtb in cell and mouse models. Taken together, our data reveal that TRIM27 is a host defense factor against Mtb, and the TRIM27-CREB1-TFEB axis is a potential HDT-based TB target that can enhance host autophagy flux.: ATG5: autophagy related 5; BMDMs: bone marrow-derived macrophages; CFU: colony-forming unit; ChIP-seq: chromatin immunoprecipitation followed by sequencing; CREB1: cAMP responsive element binding protein 1; CTSB: cathepsin B; E3: ubiquitin ligase; EMSA: electrophoretic mobility shift assay; HC: healthy control; HDT: host-directed therapy; LAMP: lysosomal associated membrane protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TPR cation channel 1; Mtb: ; NLS: nuclear localization signal; PBMCs: peripheral blood mononuclear cells; PRKA/PKA: protein kinase cAMP-activated; qRT-PCR: quantitative real-time PCR; RFP: RET finger protein; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TRIM: tripartite motif; TSS: transcription start site; ULK1: unc-51 like autophagy activating kinase 1.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210901 | PMC |
| http://dx.doi.org/10.1080/15548627.2024.2321831 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Cardioprotective effects of the electrolyte solution sterofundin and the possible underlying mechanisms.
Front Pharmacol
January 2025
Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background: Sterofundin (SF) is one of the most widely used electrolyte solutions in almost all areas of medicine, with particular importance in intensive care. It provides powerful correction of acid-base imbalances, ion fluctuations, and impaired energy metabolism, which are the three most important characteristics after myocardial infarction (MI). However, whether and how SF protects the heart from post-MI damage are largely unknown.
View Article and Find Full Text PDFHypoxia-Inducible Factor-1α Regulates BNIP3-Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion.
J Biochem Mol Toxicol
February 2025
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Objective: Gliomas are the predominant form of malignant brain tumors. We investigated the mechanism of hypoxia-inducible factor-1α (HIF-1α) affecting glioma metabolic reprogramming, proliferation and invasion.
Methods: Human glioma cell U87 was cultured under hypoxia and treated with small interfering (si)HIF-1α, si-B cell lymphoma-2/adenovirus E1B 19-kDa interacting protein 3 (siBNIP3), si-YT521-B homology domain 2 (siYTHDF2), 3-methyladenine and 2-deoxyglucose, with exogenous sodium lactate-treated normally-cultured cells as a lactate-positive control.
Enhancing hepatocellular carcinoma therapy with DOX-loaded SiO nanoparticles via mTOR-TFEB pathway autophagic flux inhibition.
J Nanobiotechnology
January 2025
Imaging Center, The Third Affiliated Hospital of Anhui Medical University, Hefei, 230061, China.
Chemotherapeutic drugs often fail to provide long-term efficacy due to their lack of specificity and high toxicity. To enhance the biosafety and reduce the side effects of these drugs, various nanocarrier delivery systems have been developed. In this study, we loaded the anticancer drug doxorubicin (DOX) and an MRI contrast agent into silica nanoparticles, coating them with pH-responsive and tumor cell-targeting polymers.
View Article and Find Full Text PDFOxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway.
Phytomedicine
January 2025
The State Key Laboratory of Functions and Applications of Medicinal Plants (The Key Laboratory of Endemic and Ethnic Diseases of Ministry of Education), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province (The high educational key laboratory of Guizhou province for natural medicianl Pharmacology and Druggability), Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China; The Department of Pharmacology of Materia Medica, School of Pharmaceutical Sciences, Guizhou Medical University, No.6 Ankang Avenue, Guiyang City and Guian New District, Guizhou 561113, China. Electronic address:
Background: Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy.
View Article and Find Full Text PDFThe anti-senescence effect of D-β-hydroxybutyrate in Hutchinson-Gilford progeria syndrome involves progerin clearance by the activation of the AMPK-mTOR-autophagy pathway.
Geroscience
January 2025
Department of Neuropathology, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), 04510, Mexico City, Mexico.
D-β-hydroxybutyrate, BHB, has been previously proposed as an anti-senescent agent in vitro and in vivo in several tissues including vascular smooth muscle. Moreover, BHB derivatives as ketone esters alleviate heart failure. Here, we provide evidence of the potential therapeutic effect of BHB on Hutchinson-Gilford progeria syndrome (HGPS), a rare condition characterized by premature aging and heart failure, caused by the presence of progerin, the aberrant protein derived from LMNA/C gene c.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!