New regulators of autophagy
Highly regulated, autophagy enables cells to survive stresses such as starvation. In the process, cytoplasmic proteins and organelles are sequestered in vesicles called autophagosomes. Fusion of autophagosomes with lysosomes results in degradation of their content, followed by recycling of the nutrients and molecular building blocks in the cytosol. Autophagy also helps remove toxic macromolecules and damaged organelles from the body. Preliminary studies identified short coiled-coil protein (SCOC), a small Golgi protein, as a regulator of starvation-induced autophagosome formation. SCOC interacts through fasciculation and elongation protein zeta-1 (FEZ1) with kinase complexes regulating autophagosome formation and maturation. Mutation analysis implicated SCOC, FEZ1 and associated kinases in the regulation of the developing nervous system. The EU-funded SCOC AND FEZ (Functional analysis of SCOC and FEZ proteins in autophagy using mammalian cell models and zebrafish) project investigated biological function of SCOC and FEZ1 proteins in autophagy using a multidisciplinary approach. Researchers employed structural analyses to study the interaction of SCOC with FEZ1. Analysis of the crystal structure of SCOC at a resolution of 2.1Å showed that SCOC forms a parallel dimer. Biochemical and biophysical analyses allowed them to map the binding site of FEZ1 and SCOC and learn more about amino acids involved in their interaction. Biochemical and cell biological analyses of kinase complexes suggested that SCOC and FEZ1 regulate recruitment of these complexes to autophagosome formation sites. Researchers initiated the development of a zebrafish model system as an alternative to mammalian models to study autophagy. Zebrafish has proven to be an excellent vertebrate model system to study development and human disease. Gene expression analyses showed that SCOC and FEZ1 are present in early embryonic developmental stages in zebrafish. Project researchers focused on the investigation of phenotypes that affect early zebrafish development to test whether these are caused by defects in autophagy. Study outcomes could provide invaluable insight into factors affecting autophagy in health and disease. This has significant implications for the future of biomedicine.
Keywords
Autophagy, starvation, autophagosome, SCOC AND FEZ, zebrafish
