Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UMLS:C0018801 (
heart failure
)
72,216
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Coxsackievirus B3 (CVB3) is an important human pathogen linked to cardiac arrhythmias and acute
heart failure
. CVB3 infection has been reported to induce the formation of autophagosomes that support the viral replication in host cells. Interestingly, our study shows that the accumulation of autophagosomes during CVB3 infection is caused by a blockage of autophagosome-lysosome fusion rather than the induction of autophagosome biogenesis. Moreover, CVB3 decreases the transcription and translation of
syntaxin 17
(
STX17
), a SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein involved in autophagosome-lysosome fusion. Overexpression of
STX17
restored the autophagic flux, alleviated the virus-induced lysosomal dysfunction, and decreased the apoptosis induced by CVB3 infection in HeLa cells. Taken together, our results suggest that CVB3 infection impairs the autophagic flux by blocking autophagosome-lysosome fusion. These findings thus point to potential new therapeutic strategies targeting
STX17
or autophagosome-lysosome fusion for treating CVB3-associated diseases.
...
PMID:The cytotoxicity of coxsackievirus B3 is associated with a blockage of autophagic flux mediated by reduced syntaxin 17 expression. 2944 55
Mutations in lysosomal-associated membrane protein 2 (
LAMP-2
) gene are associated with Danon disease, which often leads to cardiomyopathy/
heart failure
through poorly defined mechanisms. Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome-lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of
syntaxin 17
(
STX17
), a protein that is essential for autophagosome-lysosome fusion in non-CMs. Instead, LAMP-2B interacts with autophagy related 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal coiled coil domain (CCD) to promote autophagic fusion. CMs derived from induced pluripotent stem cells (hiPSC-CMs) from Danon patients exhibit decreased colocalization between ATG14 and VAMP8, profound defects in autophagic fusion, as well as mitochondrial and contractile abnormalities. This phenotype was recapitulated by
LAMP-2B
knockout in non-Danon hiPSC-CMs. Finally, gene correction of
LAMP-2
mutation rescues the Danon phenotype. These findings reveal a
STX17
-independent autophagic fusion mechanism in human CMs, providing an explanation for cardiomyopathy in Danon patients and a foundation for targeting defective LAMP-2B-mediated autophagy to treat this patient population.
...
PMID:LAMP-2B regulates human cardiomyocyte function by mediating autophagosome-lysosome fusion. 3058 88
