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Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements
Journal article   Open access   Peer reviewed

Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements

Jae Ho Seo, Ekta Agarwal, Kelly G Bryant, M Cecilia Caino, Eui Tae Kim, Andrew V Kossenkov, Hsin-Yao Tang, Lucia R Languino, Dmitry I Gabrilovich, Andrew R Cohen, …
Cancer research (Chicago, Ill.), v 78(15), pp 4215-4228
01 Aug 2018
DOI: https://doi.org/10.1158/0008-5472.CAN-18-0595
PMID: 29898993
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/0008-5472.can-18-0595View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Cell Line Cell Line, Tumor Cell Movement - physiology Cytoskeleton - metabolism Cytoskeleton - physiology Dynamins - metabolism Humans Male Membrane Proteins Mice Mice, Inbred C57BL Mitochondria - metabolism Mitochondria - pathology Mitochondrial Dynamics - physiology Neoplasms - metabolism Neoplasms - pathology Nerve Tissue Proteins - metabolism NIH 3T3 Cells PC-3 Cells Ubiquitin-Protein Ligases - metabolism Ubiquitination - physiology Vesicular Transport Proteins - metabolism
Syntaphilin (SNPH) inhibits the movement of mitochondria in tumor cells, preventing their accumulation at the cortical cytoskeleton and limiting the bioenergetics of cell motility and invasion. Although this may suppress metastasis, the regulation of the SNPH pathway is not well understood. Using a global proteomics screen, we show that SNPH associates with multiple regulators of ubiquitin-dependent responses and is ubiquitinated by the E3 ligase CHIP (or STUB1) on Lys111 and Lys153 in the microtubule-binding domain. SNPH ubiquitination did not result in protein degradation, but instead anchored SNPH on tubulin to inhibit mitochondrial motility and cycles of organelle fusion and fission, that is dynamics. Expression of ubiquitination-defective SNPH mutant Lys111→Arg or Lys153→Arg increased the speed and distance traveled by mitochondria, repositioned mitochondria to the cortical cytoskeleton, and supported heightened tumor chemotaxis, invasion, and metastasis Interference with SNPH ubiquitination activated mitochondrial dynamics, resulting in increased recruitment of the fission regulator dynamin-related protein-1 (Drp1) to mitochondria and Drp1-dependent tumor cell motility. These data uncover nondegradative ubiquitination of SNPH as a key regulator of mitochondrial trafficking and tumor cell motility and invasion. In this way, SNPH may function as a unique, ubiquitination-regulated suppressor of metastasis. These findings reveal a new mechanism of metastasis suppression by establishing the role of SNPH ubiquitination in inhibiting mitochondrial dynamics, chemotaxis, and metastasis. .

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47 citations in Web of Science
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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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