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Targeting the Lysosomal Degradation of Rab22a-NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis

Cuiling Zeng1, Li Zhong2,3, Wenqiang Liu1,4

  • 1State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 18, 2022
PubMed

Insights

The Rab22a-NeoF1 fusion protein, a target for osteosarcoma lung metastasis, is degraded by STUB1 via lysosomes, facilitated by PINK1 kinase. This pathway can be targeted by Sorafenib and Regorafenib to inhibit metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Rab22a-NeoF fusion protein is a potential therapeutic target for osteosarcoma lung metastasis.
  • The regulatory mechanisms controlling Rab22a-NeoF1 levels within cells were previously unknown.

Purpose of the Study:

  • To elucidate the cellular regulation and degradation pathways of the Rab22a-NeoF1 fusion protein.
  • To investigate the potential of targeting this degradation pathway for therapeutic intervention in osteosarcoma.

Main Methods:

  • Utilized multiple screening techniques to identify regulatory factors.
  • Investigated the roles of E3 ligase STUB1, autophagy receptor NDP52, and PINK1 kinase in Rab22a-NeoF1 degradation.
  • Analyzed ubiquitination patterns (K63-linked chains) and phosphorylation sites (Serine 120).

Main Results:

  • Rab22a-NeoF1 is degraded via the NDP52-mediated lysosome pathway, involving the E3 ligase STUB1.
  • PINK1 kinase facilitates this degradation by phosphorylating Rab22a-NeoF1 at Serine 120, promoting ubiquitination.
  • STUB1 catalyzes K63-linked ubiquitin chains on Lysine 112, mediating Rab22a-NeoF1 binding to NDP52.
  • Upregulation of PINK1 by Sorafenib and Regorafenib inhibits osteosarcoma lung metastasis driven by Rab22a-NeoF1.

Conclusions:

  • The lysosomal degradation of Rab22a-NeoF1 is a targetable pathway for inhibiting osteosarcoma lung metastasis.
  • Sorafenib and Regorafenib show potential therapeutic benefits for patients with RAB22A-NeoF1 fusion-positive osteosarcoma.
Keywords:
degradationfusion proteinmetastasisosteosarcomaphosphorylation

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