The multiple personalities of Alix

Introduction Proteins that can regulate seemingly disparate mechanisms do so by engaging in multiple distinct protein interaction networks. Such multifunctional activities are characteristic of a protein in mammalian cells known as 'Alix' or 'AIP1'. Both names derive from its original discovery as an interaction partner of ALG-2, a Ca 2+-binding protein implicated in apoptotic signaling (Missotten et al., 1999; Vito et al., 1999). Here, I use Alix to avoid confusion with the yeast Aip1 protein that promotes severing and capping of actin filaments (Okada et al., 2006). Solid evidence supports a functional link between Alix and apoptosis, but studies have also connected Alix to endocytic membrane trafficking and cytoskeletal remodeling. In addition, several viruses exploit Alix in order to bud from infected cells (Fig. 1). The ability of Alix to participate in a spectrum of activities stems from its domain architecture (Fig. 2). Its N-terminal 'Bro1 domain' mediates localization to endosomes, a major functional site for Alix; its C-terminal region interacts with the majority of proteins that connect Alix to cellular processes. The Bro1 domain and C-terminal region are linked by a relatively uncharacterized sequence containing two coiled-coil domains. This tripartite domain organization occurs in predicted orthologues of Alix in fungi, plants, worms, flies and fish. More-divergent relatives of Alix also contain the Bro1 domain but bear little resemblance to Alix otherwise and they presumably use the Bro1 domain to associate with endosomes for unrelated purposes. The roles of Alix have largely been inferred from the functions of proteins with which it interacts. However, relatively little is known regarding the specific molecular functions of Alix in these processes. Below, I summarize the roles that have been proposed for Alix and discuss these in light of the function of yeast Bro1, which is the best characterized orthologue of Alix.