The actin cytoskeleton is adapted to many different structures and involved in diverse cellular functions. Differentiation of the cytoskeletal structures is generally controlled by a number of actin-binding proteins that regulate dynamics and organization of the actin filaments. Myofibrils in striated muscle are highly differentiated forms of the actin cytoskeleton and specialized for generating contractile forces. However, the mechanisms by which actin filaments are assembled into myofibrils during development and maintained in the contractile apparatuses are largely unknown. The nematode Caenorhabditis elegans has obliquely striated muscle in the body wall, which shares a number of biochemical and functional similarities with vertebrate striated muscle. We have identified actin depolymerizing factor (ADF)/cofilin, actin-interacting protein 1 (AIP1), and tropomyosin as key regulators of actin organization in the body wall muscle. When these proteins are defective, the actin filaments are disorganized and the contractility of the body wall muscle is impaired. In addition, we obtained evidence that UNC-87, a calponin-like protein, and kettin, immunoglobulin-like repeat protein, may stabilize actin filaments, and PFN-3, a muscle-specific profilin, may help recycling actin monomers for polymerization. Although genetic and biochemical analyses of these proteins suggest that each of these actin-binding proteins might be important for regulation of actin dynamics in muscle cells, we do not understand how these proteins functionally interact. We hypothesize that ADF/cofilin is a key enhancer of actin dynamics and functionally interacts with other actin-binding proteins to regulate actin polymerization, depolymerization, and stability during assembly and maintenance of the striated myofibrils. In this project, we aim to investigate mechanisms of three aspects of actin dynamics in muscle cells in C. elegans:
(Aim 1) To determine how ADF/cofilin and AIP1 disassemble actin filaments in muscle cells, (Aim 2) To determine how actin monomers are recycled for polymerization in muscle cells, and (Aim 3) To determine how actin filaments are stabilized in muscle cells. These studies should provide important information not only on the mechanism of normal myofibril assembly and maintenance but also on the pathogenesis of nemaline myopathy in which misregulation of actin filament stability is implicated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048615-10
Application #
8118199
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2002-05-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
10
Fiscal Year
2011
Total Cost
$306,381
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ono, Shoichiro (2017) A plague of actin disassembly. J Biol Chem 292:8101-8102
Iwase, Shohei; Ono, Shoichiro (2017) Conserved hydrophobic residues in the CARP/?-sheet domain of cyclase-associated protein are involved in actin monomer regulation. Cytoskeleton (Hoboken) 74:343-355
Ono, Shoichiro (2017) Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation. Biochem Biophys Res Commun :
Hwang, Hyundoo; Barnes, Dawn E; Matsunaga, Yohei et al. (2016) Muscle contraction phenotypic analysis enabled by optogenetics reveals functional relationships of sarcomere components in Caenorhabditis elegans. Sci Rep 6:19900
Barnes, Dawn E; Hwang, Hyundoo; Ono, Kanako et al. (2016) Molecular evolution of troponin I and a role of its N-terminal extension in nematode locomotion. Cytoskeleton (Hoboken) 73:117-30
Ono, Kanako; Ono, Shoichiro (2016) Two distinct myosin II populations coordinate ovulatory contraction of the myoepithelial sheath in the Caenorhabditis elegans somatic gonad. Mol Biol Cell 27:1131-42
Lee, Cho-Yin; Lou, Jizhong; Wen, Kuo-Kuang et al. (2016) Regulation of actin catch-slip bonds with a RhoA-formin module. Sci Rep 6:35058
Nomura, Kazumi; Hayakawa, Kimihide; Tatsumi, Hitoshi et al. (2016) Actin-interacting Protein 1 Promotes Disassembly of Actin-depolymerizing Factor/Cofilin-bound Actin Filaments in a pH-dependent Manner. J Biol Chem 291:5146-56
Iwase, Shohei; Ono, Shoichiro (2016) The C-terminal dimerization motif of cyclase-associated protein is essential for actin monomer regulation. Biochem J 473:4427-4441
Shukla, Vaibhav Kumar; Kabra, Ashish; Maheshwari, Diva et al. (2015) Solution structures and dynamics of ADF/cofilins UNC-60A and UNC-60B from Caenorhabditis elegans. Biochem J 465:63-78

Showing the most recent 10 out of 49 publications