LLPS of SQSTM1/p62 and NBR1 as outcomes of lysosomal stress response limits cancer cell metastasis
Takuya Noguchi, Yuto Sekiguchi, Tatsuya Shimada, Wakana Suzuki, Takumi Yokosawa, T. Itoh, Mayuka Yamada, Midori Suzuki, Reon Kurokawa, Yusuke Hirata, Atsushi Matsuzawa
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.