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Syntaphilin Ubiquitination Regulates Mitochondrial Dynamics and Tumor Cell Movements

Jae Ho Seo1,2, Ekta Agarwal1,2, Kelly G Bryant1,2

  • 1Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania.

Cancer Research
|June 15, 2018
PubMed

Insights

Syntaphilin (SNPH) ubiquitination by CHIP regulates mitochondrial movement, suppressing tumor cell invasion and metastasis. Disrupting this process enhances mitochondrial motility and tumor spread.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Syntaphilin (SNPH) is known to inhibit mitochondrial movement in tumor cells, potentially suppressing metastasis.
  • The regulatory mechanisms governing the SNPH pathway, particularly its role in metastasis, remain largely unelucidated.

Purpose of the Study:

  • To investigate the regulation of Syntaphilin (SNPH) and its role in controlling mitochondrial dynamics and tumor cell invasion.
  • To identify the specific ubiquitination events on SNPH and their functional consequences.

Main Methods:

  • Global proteomics screening to identify SNPH-interacting proteins.
  • Site-directed mutagenesis to create ubiquitination-defective SNPH mutants.
  • Live-cell imaging to track mitochondrial motility.
  • In vivo studies to assess tumor chemotaxis, invasion, and metastasis.

Main Results:

  • SNPH is ubiquitinated by the E3 ligase CHIP (STUB1) at Lys111 and Lys153, anchoring it to tubulin.
  • This non-degradative ubiquitination inhibits mitochondrial motility and dynamics, suppressing tumor cell invasion and metastasis.
  • Mutations preventing SNPH ubiquitination increased mitochondrial motility, cortical localization, and promoted tumor metastasis in vivo.
  • Interference with SNPH ubiquitination enhanced mitochondrial dynamics, leading to increased dynamin-related protein-1 (Drp1) recruitment and tumor cell motility.

Conclusions:

  • Non-degradative ubiquitination of SNPH by CHIP is a critical regulator of mitochondrial trafficking.
  • SNPH ubiquitination acts as a metastasis suppressor by controlling mitochondrial dynamics and tumor cell invasion.
  • This pathway represents a novel mechanism for regulating metastasis and offers potential therapeutic targets.

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