Dysregulation of protein modification by ISG15 results in brain cell injury.
UBP43 (USP18) is a protease that removes the ubiquitin-like modifier ISG15 from conjugated proteins. Here we present the first report of dysregulation of protein ISG15 modification by the generation of UBP43 knockout mice. In the absence of UBP43, brain tissue showed an elevated level of ISG15 conjugates, and cellular necrosis was evident in the ependyma. Such disruption of the blood-brain barrier resulted in severe neurologic disorders. These results demonstrate that UBP43 plays a critical role in maintaining the homeostatic balance of ISG15-conjugated protein, and that regulation of cellular levels of ISG15 protein modification is essential for brain cell function.
Ritchie
Kenneth J
KJ
Department of Molecular and Experimental Medicine, MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Malakhov
Michael P
MP
Hetherington
Christopher J
CJ
Zhou
Liming
L
Little
Marie-Terese
MT
Malakhova
Oxana A
OA
Sipe
Jack C
JC
Orkin
Stuart H
SH
Zhang
Dong-Er
DE
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism*; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004805:Ependyma / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006849:Hydrocephalus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins
D016207:Cytokines; C489550:G1p2 protein, mouse; D012333:RNA, Messenger; D014452:Ubiquitins; D010450:Endopeptidases; C118306:Usp18 protein, mouse; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase