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1.
Mol Ther ; 30(2): 606-620, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-34601133

RESUMEN

Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.


Asunto(s)
Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Animales , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Comunicación , Vesículas Extracelulares/metabolismo , Hepatocitos/metabolismo , Células Asesinas Naturales/metabolismo , Neoplasias Hepáticas/metabolismo , Ratones , Microambiente Tumoral
2.
Nat Commun ; 15(1): 4162, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38755139

RESUMEN

The multibasic furin cleavage site at the S1/S2 boundary of the spike protein is a hallmark of SARS-CoV-2 and plays a crucial role in viral infection. However, the mechanism underlying furin activation and its regulation remain poorly understood. Here, we show that GalNAc-T3 and T7 jointly initiate clustered O-glycosylations in the furin cleavage site of the SARS-CoV-2 spike protein, which inhibit furin processing, suppress the incorporation of the spike protein into virus-like-particles and affect viral infection. Mechanistic analysis reveals that the assembly of the spike protein into virus-like particles relies on interactions between the furin-cleaved spike protein and the membrane protein of SARS-CoV-2, suggesting a possible mechanism for furin activation. Interestingly, mutations in the spike protein of the alpha and delta variants of the virus confer resistance against glycosylation by GalNAc-T3 and T7. In the omicron variant, additional mutations reverse this resistance, making the spike protein susceptible to glycosylation in vitro and sensitive to GalNAc-T3 and T7 expression in human lung cells. Our findings highlight the role of glycosylation as a defense mechanism employed by host cells against SARS-CoV-2 and shed light on the evolutionary interplay between the host and the virus.


Asunto(s)
COVID-19 , Furina , Mutación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/química , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Glicosilación , Furina/metabolismo , Furina/genética , COVID-19/virología , COVID-19/metabolismo , Células HEK293 , N-Acetilgalactosaminiltransferasas/metabolismo , N-Acetilgalactosaminiltransferasas/genética , Animales , Chlorocebus aethiops , Polipéptido N-Acetilgalactosaminiltransferasa
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