TACC3-TSC2 maintains nuclear envelope structure and controls cell division.

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Tuberous sclerosis complex (TSC) proteins (TSC1/TSC2) are known regulators of translation and cell growth.
• The role of TSC proteins in cellular structure and cell cycle regulation is not fully understood.
• Transforming acidic coiled-coil (TACC) domain proteins are involved in centrosome-associated structures and processes.

Purpose of the Study:

• To investigate the interaction between TACC3 and TSC2.
• To elucidate the role of TACC3 and TSC2 in cellular structures and cell division.
• To explore the implications for lymphangioleiomyomatosis (LAM) and TSC syndrome.

Main Methods:

• Interactome mapping to identify TACC3 binding partners.
• Co-localization and co-purification studies with nuclear envelope components.
• Analysis of cell division, including spindle pole localization, abscission, and binucleation in Tacc3- and Tsc2-deficient cells.

Main Results:

• TACC3 interactome mapping identified TSC2 and 15 other proteins, including ch-TOG/CKAP5 and FAM161B.
• TACC3 and TSC2 co-localize with nuclear envelope components, and their deficiency causes nuclear envelope morphological alterations.
• TACC3 is essential for proper phospho-Ser939 TSC2 localization during cell division, and Tacc3/Tsc2 deficiency leads to abscission defects and increased binucleation.

Conclusions:

• TACC3 links to novel structural and cell division functions of TSC2.
• TSC2 acts epistatically to TACC3 in cell division regulation, converging on the CHFR-mediated mitotic checkpoint.
• These findings provide potential explanations for the clinical manifestations of LAM and TSC, including the differential severity of TSC1 versus TSC2 mutations.