title: Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke.
abstract: Ubiquitin-modification of proteins by E3 ubiquitin ligases is an important post-translational mechanism implicated in neuronal survival and injury following cerebral ischemia. However, of the 500 or so E3s thought to be present in mammalian cells, very few specific E3s have been identified and associated with brain ischemia. Here, we demonstrate endogenous induction of HECT-type E3 ligases of the Nedd4 family and their adaptor Nedd4-family interacting protein 1 (Ndfip1) following transient focal cerebral ischemia in rats. Ndfip1 is upregulated in surviving cortical neurons and its neuroprotective activity is correlated with Nedd4-2 upregulation, but not two other Nedd4 family members examined (Nedd4-1 and Itch). Immunoprecipitation assays confirmed biochemical binding of Ndfip1 with Nedd4-2 in the brain, with or without ischemic stroke, indicating their endogenous interaction. While Ndfip1 and Itch have been previously shown to interact outside of the nervous system, ischemic induction of Itch in the present study was associated with cellular survival independent of Ndfip1. Together, these findings demonstrate specific and differential regulation of Nedd4 family E3 ligases under ischemic conditions, and identify two E3 ligases and their adaptor that potentially regulate ubiquitination in ischemic stroke to provide neuroprotection.
authors.affiliation: Brain Development and Regeneration Laboratory, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lackovic
authors.forename: Jason
authors.initials: J
authors.lastname: Howitt
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Callaway
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Perry
authors.initials: P
authors.lastname: Bartlett
authors.forename: Seong-Seng
authors.initials: SS
authors.lastname: Tan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases