Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells

Autor(en)

Enrico Desideri, Serena Castelli, Coralie Dorard, Stefanie Toifl, Gian Luca Grazi, Maria Rosa Ciriolo, Manuela Baccarini

Abstrakt

Impaired degradation of the transcriptional coactivator YAP1 and IL6ST (interleukin 6 cytokine family signal transducer), two proteins deregulated in liver cancer, has been shown to promote tumor growth. Here, we demonstrate that YAP1 and IL6ST are novel substrates of chaperone-mediated autophagy (CMA) in human hepatocellular carcinoma (HCC) and hepatocyte cell lines. Knockdown of the lysosomal CMA receptor LAMP2A increases protein levels of YAP1 and IL6ST, without changes in mRNA expression. Additionally, both proteins show KFERQ-dependent binding to the CMA chaperone HSPA8 and accumulate into isolated lysosomes after stimulation of CMA by prolonged starvation. We further show that LAMP2A downregulation promotes the proliferation and migration in HCC cells and a human hepatocyte cell line, and that it does so in a YAP1- and IL6ST-dependent manner. Finally, LAMP2A expression is downregulated, and YAP1 and IL6ST expression is upregulated, in human HCC biopsies. Taken together, our work reveals a novel mechanism that controls the turnover of two cancer-relevant proteins and suggests a tumor suppressor function of CMA in the liver, advocating for the exploitation of CMA activity for diagnostic and therapeutic purposes.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; CMA: chaperone-mediated autophagy; eMI: endosomal microautophagy; HCC: hepatocellular carcinoma; HSPA8: heat shock protein family A (Hsp70) member 8; IL6ST: interleukin 6 cytokine family signal transducer; JAK: Janus kinase; LAMP1: lysosomal associated membrane protein 1; LAMP2A: lysosomal associated membrane protein 2A; MAPK8: mitogen-activated protein kinase 8; P6: pyridine 6; SQSTM1: sequestosome 1; TUBA: tubulin alpha; VDAC1: voltage dependent anion channel 1; VP: verteporfin; YAP1: Yes1 associated transcriptional regulator.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

Università degli Studi di Roma "Tor Vergata", Regina Elena Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico

Journal

Autophagy

Band

19

Seiten

152-162

Anzahl der Seiten

11

ISSN

1554-8627

DOI

https://doi.org/10.1080/15548627.2022.2063004

Publikationsdatum

01-2023

Peer-reviewed

Ja

ÖFOS 2012

106023 Molekularbiologie, 106052 Zellbiologie

Schlagwörter

ASJC Scopus Sachgebiete

Molecular Biology, Cell Biology

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/impaired-degradation-of-yap1-and-il6st-by-chaperonemediated-autophagy-promotes-proliferation-and-migration-of-normal-and-hepatocellular-carcinoma-cells(f93221b6-4ac4-4cc9-b28b-ae2ac0df0e2b).html