TACC3-TSC2 maintains nuclear envelope structure and controls cell division.
Studies of the role of tuberous sclerosis complex (TSC) proteins (TSC1/TSC2) in pathology have focused mainly on their capacity to regulate translation and cell growth, but their relationship with alterations of cellular structures and the cell cycle is not yet fully understood. The transforming acidic coiled-coil (TACC) domain-containing proteins are central players in structures and processes connected to the centrosome. Here, TACC3 interactome mapping identified TSC2 and 15 other physical interactors, including the evolutionary conserved interactions with ch-TOG/CKAP5 and FAM161B. TACC3 and TSC2 co-localize and co-purify with components of the nuclear envelope, and their deficiency causes morphological alterations of this structure. During cell division, TACC3 is necessary for the proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. Accordingly, abscission alterations and increased frequency of binucleated cells were observed in Tacc3- and Tsc2-deficient cells relative to controls. In regulating cell division, TSC2 acts epistatically to TACC3 and, in addition to canonical TSC/mTOR signaling and cytokinetic associations, converges to the early mitotic checkpoint mediated by CHFR, consistently with nuclear envelope associations. Our findings link TACC3 to novel structural and cell division functions of TSC2, which may provide additional explanations for the clinical and pathological manifestations of lymphangioleiomyomatosis (LAM) disease and TSC syndrome, including the greater clinical severity of TSC2 mutations compared to TSC1 mutations.
Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain.
Laia
L
Gómez-Baldó
Stephan
S
Schmidt
Christopher A
CA
Maxwell
Núria
N
Bonifaci
Toni
T
Gabaldón
Pierre-Olivier
PO
Vidalain
William
W
Senapedis
Anja
A
Kletke
Mechthild
M
Rosing
Angelika
A
Barnekow
Robert
R
Rottapel
Gabriel
G
Capellá
Marc
M
Vidal
Aristotelis
A
Astrinidis
Roland P
RP
Piekorz
Miguel Angel
MA
Pujana
D000818:Animals; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D018385:Centrosome / Q000378:metabolism; D048749:Cytokinesis; D004843:Epistasis, Genetic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D008938:Mitosis; D009685:Nuclear Envelope / Q000378:metabolism*; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D008941:Spindle Apparatus / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine