SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion.
Hum Cell
; 35(6): 1766-1784, 2022 Nov.
Article
en En
| MEDLINE
| ID: mdl-36050615
ABSTRACT
MicroRNA dysregulation is a hallmark of hepatocellular carcinoma (HCC), leading to tumor growth and metastasis. Previous screening on patient specimens identified miR-198 as the most downregulated miRNA in HCC. Here, we show that miR-198 compensation leads to self-release into extracellular vesicles (EVs). Importantly, the vesicular secretion is mediated by autophagy-related pathway, initiated by sequestration of p62/miR-198 complexes in autophagosome-associated vesicle fractions. miR-198 is selectively recognized and loaded by p62 into autophagosomal fractions, whereas mutated miR-198 forms neither induce autophagy and nor interact with p62. Gain and loss of function experiments, using a CRIPR/Cas knockout (KO) and transgenic site-specific p62 mutants, identified p62 as an essential repressor of cellular miR-198 abundancy. Notably, EVs, harboring miR-198/p62 protein complexes, can be uptaken by cells in the close vicinity, leading to change of gene expression in recipient cells. In conclusion, miR-198 enhances autophagy; conversely autophagic protein p62 reduces the miR-198 levels by sorting into extracellular space. miR-198 is at first transcribed as primary miRNA, after being processed into single stranded mature miR-198 form, it is transported into cytoplasm â . By interaction with p62 protein, miR-198 conglomerates and forms a binding complex â¡. Since LC3 protein is an interaction partner of p62 protein, hence miR-198 is included into autophagosomes â¢. By fusion with multivesicular bodies (MVB), miR-198-binding complex was recruited into amphisomes â£, the latter of which quickly turns into secretory MVB containing intraluminal vesiclesâ¤. By fusion with cell membrane, intraluminal vesicles were released into extracellular space as EVs â¥.
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Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Carcinoma Hepatocelular
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MicroARNs
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Vesículas Extracelulares
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Neoplasias Hepáticas
Límite:
Humans
Idioma:
En
Revista:
Hum Cell
Año:
2022
Tipo del documento:
Article
País de afiliación:
Alemania