セミナー情報

Many cellular processes involved in shape, motility, division and membrane dynamics rely upon spatially and temporally regulated actin filaments. This regulation involves not only actin assembly and disassembly but also myosin-mediated movement along and contraction of actin filaments. Every eukaryotic cell that uses actin expresses a member of the actin depolymerizing factor (ADF)/cofilin (AC) family. Mammals express three isoforms that share ~70% sequence identity and strong structural homology but which have subtle functional differences. ADF and cofilin-1 have a higher affinity for ADP-actin compared to ATP- or ADP∙Pi-actin and can sever filaments without capping the newly generated ends, enhancing actin dynamics. A family of structurally similar proteins known as GMFs, have evolved to target filaments branched by the actin related protein (Arp)2/3 complex and function in de-branching. AC proteins play especially important roles in the development and function of the nervous system. AC proteins are regulated by phosphorylation on ser3 through both regulated kinases and phosphatases. Other forms of regulation, such as oxidation, have also been found which can change the target of cofilin-1 from actin to mitochondria, triggering a cofilin-dependent apoptotic pathway. AC proteins also can bind cooperatively along actin filaments and compete with myosin II, thus regulating actomyosin contractility separately from myosin phosphorylation by MLCK. Cooperative binding of AC to F-actin coupled with severing generates in cells small filaments with a 1:1 actin:AC composition that bundle under conditions of oxidative stress to form inclusions (cofilin-actin rods) in axons and dendrites of neurons. Multiple age/disease-related pathways for AC overexpression or activation (dephosphorylation) have been identified in neurons. At least two different pathways have been identified for production of reactive oxygen required for neuronal rod formation. One pathway, probably involved in rods produced during ischemic injury, involves mitochondrial produced reactive oxygen species (ROS). A second pathway triggered by amyloid-β and proinflammatory cytokines is dependent on cellular prion protein/NADPH oxidase activity. Rods affect synaptic function and may play important roles in neurodegenerative disorders.