LLPS of SQSTM1/p62 and NBR1 as outcomes of lysosomal stress response limits cancer cell metastasis

被引：21

作者：

Noguchi, Takuya ^{[1
]}

Sekiguchi, Yuto ^{[1
]}

Shimada, Tatsuya ^{[1
]}

Suzuki, Wakana ^{[1
]}

Yokosawa, Takumi ^{[1
]}

Itoh, Tamaki ^{[1
]}

Yamada, Mayuka ^{[1
]}

Suzuki, Midori ^{[1
]}

Kurokawa, Reon ^{[1
]}

Hirata, Yusuke ^{[1
]}

Matsuzawa, Atsushi ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Pharmaceut Sci, Lab Hlth Chem, Sendai 9808578, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 43期

基金：

日本学术振兴会;

关键词：

p62; NBR1; LLPS; cancer metastasis; lysosomal stress; PHASE-SEPARATION; SELECTIVE AUTOPHAGY; IAP PROTEINS; P62; MIGRATION; CIAP1; APOPTOSIS; PHOSPHORYLATION; AMPLIFICATION; AGGREGATION;

D O I：

10.1073/pnas.2311282120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Liquid droplet has emerged as a flexible intracellular compartment that modulates var-ious cellular processes. Here, we uncover an antimetastatic mechanism governed by the liquid droplets formed through liquid-liquid phase separation (LLPS) of SQSTM1/ p62 and neighbor of BRCA1 gene 1 (NBR1). Some of the tyrosine kinase inhibitors (TKIs) initiated lysosomal stress response that promotes the LLPS of p62 and NBR1, resulting in the spreading of p62/NBR1 liquid droplets. Interestingly, in the p62/ NBR1 liquid droplet, degradation of RAS- related C3 botulinum toxin substrate 1 was accelerated by cellular inhibitor of apoptosis protein 1, which limits cancer cell motility. Moreover, the antimetastatic activity of the TKIs was completely overrid-den in p62/NBR1 double knockout cells both in vitro and in vivo. Thus, our results demonstrate a function of the p62/NBR1 liquid droplet as a critical determinant of cancer cell behavior, which may provide insight into both the clinical and biological significance of LLPS.

引用

页数：12

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