期刊
JOURNAL OF CELL SCIENCE
卷 124, 期 15, 页码 2631-2641出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.084343
关键词
Filamin; ASB2; Calponin homology domain; Ubiquitylation
类别
资金
- GlaxoSmithKline
- National Institutes of Health [RO1 GM-068600]
- American Heart Association
- Centre National de la Recherche Scientifique
- Universite Paul Sabatier
- Comite Leucemie de la Fondation de France
- Association pour la Recherche sur le Cancer
- Lady TATA Foundation
Filamins are an important family of actin-binding and crosslinking proteins that mediate remodeling of the actin cytoskeleton and maintain extracellular matrix connections by anchoring transmembrane proteins to actin filaments and linking them to intracellular signaling cascades. We recently found that filamins are targeted for proteasomal degradation by the E3 ubiquitin ligase specificity subunit ASB alpha and that acute degradation of filamins through this ubiquitin-proteasome pathway correlates with cell differentiation. Specifically, in myeloid leukemia cells retinoic-acid-induced expression of ASB2 alpha triggers filamin degradation and recapitulates early events crucial for cell differentiation. ASB2 alpha is thought to link substrates to the ubiquitin transferase machinery; however, the mechanism by which ASB2 alpha interacts with filamin to induce degradation remained unknown. Here, we use cell-based and biochemical assays to show that the subcellular localization of ASB2 alpha to actin-rich structures is dependent on filamin and that the actin-binding domain (ABD) of filamin mediates the interaction with ASB2 alpha. Furthermore, we show that the ABD is necessary and sufficient for ASB2 alpha-mediated filamin degradation. We propose that ASB2 alpha exerts its effect by binding the ABD and mediating its polyubiquitylation, so targeting filamins for degradation. These studies provide the molecular basis for ASB2 alpha-mediated filamin degradation and unravel an important mechanism by which filamin levels can be acutely regulated.
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