Details

Autor(en) / Beteiligte

• Aguilar, Areli
• Wagstaff, Kylie M.
• Suárez‐Sánchez, Rocío
• Zinker, Samuel
• Jans, David A.
• Cisneros, Bulmaro

Titel

Nuclear localization of the dystrophin‐associated protein α‐dystrobrevin through importin α2/β1 is critical for interaction with the nuclear lamina/maintenance of nuclear integrity

Ist Teil von

• The FASEB journal, 2015-05, Vol.29 (5), p.1842-1858

Ort / Verlag

United States: Federation of American Societies for Experimental Biology

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• ABSTRACT Although α‐dystrobrevin (DB) is assembled into the dystrophin‐associated protein complex, which is central to cytoskeletal organization, it has also been found in the nucleus. Here we delineate the nuclear import pathway responsible for nuclear targeting of α‐DB for the first time, together with the importance of nuclear α‐DB in determining nuclear morphology. We map key residues of the nuclear localization signal of α‐DB within the zinc finger domain (ZZ) using various truncated versions of the protein, and site‐directed mutagenesis. Pulldown, immunoprecipitation, and AlphaScreen assays showed that the importin (IMP) α2/β1 heterodimer interacts with high affinity with the ZZ domain of α‐DB. In vitro nuclear import assays using antibodies to specific importins, as well as in vivo studies using siRNA or a dominant negative importin construct, confirmed the key role of IMPα2/β1in α‐DB nuclear translocation. Knockdown of α‐DB expression perturbed cell cycle progression in C2C12 myoblasts, with decreased accumulation of cells in S phase and, significantly, altered localization of lamins A/C, B1, and B2 with accompanying gross nuclear morphology defects. Because α‐DB interacts specifically with lamin B1 in vivo and in vitro, nuclear α‐DB would appear to play a key role in nuclear shape maintenance through association with the nuclear lamina.—Aguilar, A., Wagstaff, K. M., Suárez‐Sánchez, R., Zinker, S., Jans, D. A., Cisneros, B. Nuclear localization of the dystrophin‐associated protein α‐dystrobrevin through importin α2/β1 is critical for interaction with the nuclear lamina/maintenance of nuclear integrity. FASEB J. 29, 1842‐1858 (2015). www.fasebj.org