TBC1D22B Regulates ER-to-Golgi Trafficking via RAB1B Inactivation and Promotes Oncogenic Programs in Breast Cancer

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• TBC1D22B is a GTPase-activating protein (GAP) linked to poor prognosis in breast cancer (BC).
• Understanding TBC1D22B's molecular interactions and functions is crucial for BC research.

Purpose of the Study:

• To define the TBC1D22B interactome in breast cancer cells.
• To elucidate the functional role of TBC1D22B in ER-to-Golgi transport and breast cancer progression.

Main Methods:

• Utilized proximity-labeling and co-immunoprecipitation proteomics to identify TBC1D22B interactors.
• Employed the Retention Using Selective Hooks (RUSH) system for functional assays of ER-to-Golgi transport.
• Conducted mechanistic studies targeting RAB1B and transcriptomic profiling.

Main Results:

• Identified TBC1D22B interactors enriched in ER-Golgi trafficking, endosomal transport, and adhesion pathways.
• Demonstrated TBC1D22B's GAP-dependent inhibition of ER-to-Golgi transport via direct targeting of RAB1B.
• Showed TBC1D22B promotes spheroid growth and represses extracellular matrix/adhesion genes, a signature observed in Luminal BC.

Conclusions:

• TBC1D22B regulates ER-to-Golgi trafficking through RAB1B.
• TBC1D22B contributes to oncogenic transcriptional remodeling and tumor growth in breast cancer.
• TBC1D22B represents a potential therapeutic target in breast cancer.