A decrease in the export of nascent proteins from the endoplasmic reticulum with aging may shorten cell life by two mechanisms: 1) initiation of ER stress responses, leading to enhanced apoptosis, and 2) secretion and trafficking of proteins, such as cytokines and their receptors that are required for cell growth and differentiation. A hallmark of the aging processing is the accumulation of inactive proteins that have cleared by cellular degradation systems. This pool is formed by both proteins that have been misfolded and those that have been inactivated and reached the end of their biologic half-lives. Three general mechanisms could account for the accumulation of such proteins: 1) increased misfolding, 2) enhanced protein denaturation and 3) decreased function in degradation pathways. We propose that dysfunction of protein export from the endoplasmic reticulum during aging leads to protein accumulation in the ER, protein misfolding, stimulation of ER stress responses, and enhanced apoptotic cell death. This proposal will examine the role of COPII coat proteins in the age-dependent accumulation of inactive cellular proteins. Molecular export from the ER is thought to be mediated by COPII vesicles. It has been shown that an essential COPII coat component, Sec31 in yeast, is phosphorylated and its phosphorylation has been implicated in COPII vesicle budding. However, the molecular mechanisms, including the phosphorylation sites and the kinases for this phosphorylation, are unknown. Hypothesizing that the phosphorylation-dephosphorylation cycle of the coat components of COPII vesicles may regulate molecular export from the ER, we recently discovered the phosphorylation of mammalian Sec31. In this proposal, we will determine: 1) whether the cycle of phosphorylation-dephosphorylation of mammalian Sec31 regulates protein export from the ER, 2) whether trafficking of the klotho protein, as well as other cargoes, are affected by dephosphorylation of Sec31, and 3) whether there are age-associated changes in the phosphorylation of Sec31, which may correlate with potential age-related impairment of the early secretory pathway. The success of this study will lead to a further understanding of the molecular mechanisms of aging, which may contribute to cures for age-related diseases. ? ? ? ?
|Koreishi, Mayuko; Yu, Sidney; Oda, Mayumi et al. (2013) CK2 phosphorylates Sec31 and regulates ER-To-Golgi trafficking. PLoS One 8:e54382|
|Koreishi, Mayuko; Gniadek, Thomas J; Yu, Sidney et al. (2013) The golgin tether giantin regulates the secretory pathway by controlling stack organization within Golgi apparatus. PLoS One 8:e59821|
|Yamasaki, Akinori; Menon, Shekar; Yu, Sidney et al. (2009) mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles. Mol Biol Cell 20:4205-15|
|Rutz, Christoph; Satoh, Ayano; Ronchi, Paolo et al. (2009) Following the fate in vivo of COPI vesicles generated in vitro. Traffic 10:994-1005|
|Pan, Xiaoxiao; Luhrmann, Anja; Satoh, Ayano et al. (2008) Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science 320:1651-4|
|Satoh, Ayano; Warren, Graham (2008) In situ cleavage of the acidic domain from the p115 tether inhibits exocytic transport. Traffic 9:1522-9|