Maine Gabriel N, Mao Xicheng, Muller Patricia A, Komarck Christine M, Klomp Leo W J, Burstein Ezra
Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, U.S.A.
Biochem J. 2009 Jan 15;417(2):601-9. doi: 10.1042/BJ20080854.
COMMD {COMM [copper metabolism Murr1 (mouse U2af1-rs1 region 1)] domain-containing} proteins participate in several cellular processes, ranging from NF-kappaB (nuclear factor kappaB) regulation, copper homoeostasis, sodium transport and adaptation to hypoxia. The best-studied member of this family is COMMD1, but relatively little is known about its regulation, except that XIAP [X-linked IAP (inhibitor of apoptosis)] functions as its ubiquitin ligase. In the present study, we identified that the COMM domain of COMMD1 is required for its interaction with XIAP, and other COMMD proteins can similarly interact with IAPs. Two conserved leucine repeats within the COMM domain were found to be critically required for XIAP binding. A COMMD1 mutant which was unable to bind to XIAP demonstrated a complete loss of basal ubiquitination and great stabilization of the protein. Underscoring the importance of IAP-mediated ubiquitination, we found that long-term expression of wild-type COMMD1 results in nearly physiological protein levels as a result of increased ubiquitination, but this regulatory event is circumvented when a mutant form that cannot bind XIAP is expressed. In summary, our findings indicate that COMMD1 expression is controlled primarily by protein ubiquitination, and its interaction with IAP proteins plays an essential role.
COMMD（含COMM[铜代谢Murr1（小鼠U2af1-rs1区域1）]结构域）蛋白参与多种细胞过程，范围从核因子κB（NF-κB）调控、铜稳态、钠转运到低氧适应。该家族研究得最透彻的成员是COMMD1，但除了X连锁凋亡抑制蛋白（XIAP）作为其泛素连接酶外，对其调控了解相对较少。在本研究中，我们确定COMMD1的COMM结构域是其与XIAP相互作用所必需的，并且其他COMMD蛋白也能类似地与凋亡抑制蛋白相互作用。发现COMM结构域内的两个保守亮氨酸重复序列对于XIAP结合至关重要。一个无法与XIAP结合的COMMD1突变体表现出基础泛素化完全丧失且蛋白高度稳定。我们发现野生型COMMD1的长期表达由于泛素化增加导致接近生理水平的蛋白量，这突出了凋亡抑制蛋白介导的泛素化的重要性，但当表达不能结合XIAP的突变形式时，这一调控事件被规避。总之，我们的研究结果表明COMMD1的表达主要受蛋白泛素化控制，并且它与凋亡抑制蛋白的相互作用起着至关重要的作用。
