SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion
Yu X, Eischeid-Scholz H, Meder L, Kondylis V, Buettner R, Odenthal M (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 35
Pages Range: 1766-1784
Journal Issue: 6
DOI: 10.1007/s13577-022-00765-7
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. Graphical abstract: [Figure not available: see fulltext.] miR-198 is at first transcribed as primary miRNA, after being processed into single stranded mature miR-198 form, it is transported into cytoplasm ①. By interaction with p62 protein, miR-198 conglomerates and forms a binding complex ②. Since LC3 protein is an interaction partner of p62 protein, hence miR-198 is included into autophagosomes ③. By fusion with multivesicular bodies (MVB), miR-198-binding complex was recruited into amphisomes ④, the latter of which quickly turns into secretory MVB containing intraluminal vesicles⑤. By fusion with cell membrane, intraluminal vesicles were released into extracellular space as EVs ⑥.
Authors with CRIS profile
Involved external institutions
Germany (DE)How to cite
APA:
Yu, X., Eischeid-Scholz, H., Meder, L., Kondylis, V., Buettner, R., & Odenthal, M. (2022). SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion. Human Cell, 35(6), 1766-1784. https://dx.doi.org/10.1007/s13577-022-00765-7
MLA:
Yu, Xiaojie, et al. "SQSTM1/p62 promotes miR-198 loading into extracellular vesicles and its autophagy-related secretion." Human Cell 35.6 (2022): 1766-1784.
BibTeX: Download