Veroni, C. | bioRxiv Science

bioRxiv2025

Interaction of HS1BP3 with cortactin modulates TKS5 localisation and cancer malignancy

We have previously shown that HS1BP3 interacts with the SH3 domain of cortactin, a protein that contributes to a malignant phenotype in cancers. Here we demonstrate that high expression of HS1BP3 is predictive of poorer outcomes for gastric adenocarcinoma and triple negative breast carcinoma patients. We mapped the HS1BP3-SH3 interaction site to the third proline rich region (PRR3.1) of HS1BP3 and show that cells expressing an HS1BP3 PRR3.1 mutant failed to rescue the reduced proliferation and matrix degradation observed in HS1BP3 depleted cells. Moreover, the HS1BP3 PRR3.1 mutant was found to modulate the mRNA levels of the invadopodia scaffold protein TKS5 in gastric cancer cells and contribute to buildup of TKS5 inside multivesicular endosomes in both gastric and TNBC cells. Overall, our results highlight the importance of the direct interaction between the HS1BP3 PRR3.1 and the cortactin SH3 domain in cancer development by regulating endosomal trafficking and cytoskeleton arrangements.

cell biology↗

bioRxiv2024

SNX10 regulates the clearance of mitochondrial proteins and mitochondrial bioenergetics

We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX- IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV and the ATP synthase subunit pSu9 was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of COX-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics. eTOC summaryTrachsel-Moncho et al. identify the endosomal protein SNX10 as a modulator of piecemeal mitophagy of OXPHOS machinery components and mitochondrial homeostasis. They show that loss of SNX10 enhances mitochondrial protein degradation, reduces respiration, and increases ROS levels leading to elevated cell death in vivo.

cell biology↗