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Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements.
- Source :
-
Cancer research [Cancer Res] 2018 Aug 01; Vol. 78 (15), pp. 4215-4228. Date of Electronic Publication: 2018 Jun 13. - Publication Year :
- 2018
-
Abstract
- 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 in vivo 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. Significance: These findings reveal a new mechanism of metastasis suppression by establishing the role of SNPH ubiquitination in inhibiting mitochondrial dynamics, chemotaxis, and metastasis. Cancer Res; 78(15); 4215-28. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Line
Cell Line, Tumor
Cytoskeleton metabolism
Cytoskeleton physiology
Dynamins metabolism
Humans
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mitochondria pathology
Mitochondrial Dynamics physiology
NIH 3T3 Cells
PC-3 Cells
Ubiquitin-Protein Ligases metabolism
Cell Movement physiology
Mitochondria metabolism
Neoplasms metabolism
Neoplasms pathology
Nerve Tissue Proteins metabolism
Ubiquitination physiology
Vesicular Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 78
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 29898993
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-0595