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

Abstract

Liquid droplet has emerged as a flexible intracellular compartment that modulates various 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 overridden 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.

• Authors: Takuya Noguchi, Yuto Sekiguchi, Tatsuya Shimada, Wakana Suzuki, Takumi Yokosawa, Tamaki Itoh, Mayuka Yamada, Midori Suzuki, Reon Kurokawa, Yusuke Hirata, Atsushi Matsuzawa
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 120 Issue 43 Pg. e2311282120 (10 24 2023) ISSN: 1091-6490 [Electronic] United States
• PMID: 37847732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Sequestosome-1 Protein

Topics

• Intracellular Signaling Peptides and Proteins
• Sequestosome-1 Protein (genetics)
• Lysosomes
• Autophagy
• Neoplasms (drug therapy, genetics)