N-terminal arginylation and ubiquitin-mediated proteolysis in nerve regeneration.
Damaged sciatic nerves of rats respond to injury within minutes by activating reactions that result in the transfer RNA-mediated posttranslational addition of several amino acids to a variety of cytoplasmic proteins. For the most part, the site of addition of individual amino acids and the identity of the target proteins is not known. However, arginine, one of the amino acids added in greatest amounts, has been shown to be covalently linked to the N-terminus of acceptor proteins. In other simpler eukaryotic cells, N-terminal arginylation results in degradation of the arginylated proteins via the ubiquitin proteolytic pathway. Recent experiments have shown that when proteins, obtained from sciatic nerves 2 h after injury, are arginylated in vitro, they form high molecular weight aggregates. Other experiments have shown that these arginylated proteins are immunoreactive to a monoclonal antibody to ubiquitin. These findings suggest that following injury to the sciatic nerve, proteins which are arginylated are candidates for ubiquitin mediated proteolysis. Injury to a nerve incapable of regeneration without experimental intervention, the rat optic nerve, does not result in activation of the arginylation reactions until 6 days following injury. Based on the temporal differences in response to injury of sciatic and optic nerves (2 h vs. 6 days), we propose that the lack of arginylation following injury to the CNS is related to its inability to mount a regenerative response. The association of Arg modification of damaged proteins with the ubiquitin-mediated degradation of those proteins, suggests that regenerative failure in the CNS may be related, in part, to a failure to degrade intracellular proteins at the site of injury.
Department of Physiology, UMDNJ New Jersey Medical School, Newark 07103.
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Chakraborty
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Ingoglia
D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001369:Axons / Q000737:chemistry; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012343:RNA, Transfer / Q000032:analysis; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D014452:Ubiquitins; D012343:RNA, Transfer; D001120:Arginine