Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site
Abstract Background Neuroinflammation, typified by elevated levels of interleukin-1 (IL-1) α and β, and deficits in proteostasis, characterized by accumulation of polyubiquitinated proteins and other aggregates, are associated with neurodegenerative disease independently and through interactions of...
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doaj-1228e585af3a4aaaad3af58fadaef37e2020-12-27T12:06:01ZengBMCJournal of Neuroinflammation1742-20942019-12-0116111710.1186/s12974-019-1669-zInterleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating siteMeenakshisundaram Balasubramaniam0Paul A. Parcon1Chhanda Bose2Ling Liu3Richard A. Jones4Martin R. Farlow5Robert E. Mrak6Steven W. Barger7W. Sue T. Griffin8Department of Geriatrics, University of Arkansas for Medical SciencesDepartment of Geriatrics, University of Arkansas for Medical SciencesDepartment of Geriatrics, University of Arkansas for Medical SciencesDepartment of Geriatrics, University of Arkansas for Medical SciencesDepartment of Geriatrics, University of Arkansas for Medical SciencesDepartment of Neurology, Indiana Alzheimer Disease Center, Indiana UniversityDepartment of Pathology, University of Toledo Health Sciences CampusDepartment of Geriatrics, University of Arkansas for Medical SciencesDepartment of Geriatrics, University of Arkansas for Medical SciencesAbstract Background Neuroinflammation, typified by elevated levels of interleukin-1 (IL-1) α and β, and deficits in proteostasis, characterized by accumulation of polyubiquitinated proteins and other aggregates, are associated with neurodegenerative disease independently and through interactions of the two phenomena. We investigated the influence of IL-1β on ubiquitination via its impact on activation of the E3 ligase parkin by either phosphorylated ubiquitin (P-Ub) or NEDD8. Methods Immunohistochemistry and Proximity Ligation Assay were used to assess colocalization of parkin with P-tau or NEDD8 in hippocampus from Alzheimer patients (AD) and controls. IL-1β effects on PINK1, P-Ub, parkin, P-parkin, and GSK3β—as well as phosphorylation of parkin by GSK3β—were assessed in cell cultures by western immunoblot, using two inhibitors and siRNA knockdown to suppress GSK3β. Computer modeling characterized the binding and the effects of P-Ub and NEDD8 on parkin. IL-1α, IL-1β, and parkin gene expression was assessed by RT-PCR in brains of 2- and 17-month-old PD-APP mice and wild-type littermates. Results IL-1α, IL-1β, and parkin mRNA levels were higher in PD-APP mice compared with wild-type littermates, and IL-1α-laden glia surrounded parkin- and P-tau-laden neurons in human AD. Such neurons showed a nuclear-to-cytoplasmic translocation of NEDD8 that was mimicked in IL-1β-treated primary neuronal cultures. These cultures also showed higher parkin levels and GSK3β-induced parkin phosphorylation; PINK1 levels were suppressed. In silico simulation predicted that binding of either P-Ub or NEDD8 at a singular position on parkin opens the UBL domain, exposing Ser65 for parkin activation. Conclusions The promotion of parkin- and NEDD8-mediated ubiquitination by IL-1β is consistent with an acute neuroprotective role. However, accumulations of P-tau and P-Ub and other elements of proteostasis, such as translocated NEDD8, in AD and in response to IL-1β suggest either over-stimulation or a proteostatic failure that may result from chronic IL-1β elevation, easily envisioned considering its early induction in Down’s syndrome and mild cognitive impairment. The findings further link autophagy and neuroinflammation, two important aspects of AD pathogenesis, which have previously been only loosely related.https://doi.org/10.1186/s12974-019-1669-zIL-1βGSK3βPINK1Alzheimer’sParkinNEDD8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Meenakshisundaram Balasubramaniam Paul A. Parcon Chhanda Bose Ling Liu Richard A. Jones Martin R. Farlow Robert E. Mrak Steven W. Barger W. Sue T. Griffin |
spellingShingle |
Meenakshisundaram Balasubramaniam Paul A. Parcon Chhanda Bose Ling Liu Richard A. Jones Martin R. Farlow Robert E. Mrak Steven W. Barger W. Sue T. Griffin Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site Journal of Neuroinflammation IL-1β GSK3β PINK1 Alzheimer’s Parkin NEDD8 |
author_facet |
Meenakshisundaram Balasubramaniam Paul A. Parcon Chhanda Bose Ling Liu Richard A. Jones Martin R. Farlow Robert E. Mrak Steven W. Barger W. Sue T. Griffin |
author_sort |
Meenakshisundaram Balasubramaniam |
title |
Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site |
title_short |
Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site |
title_full |
Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site |
title_fullStr |
Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site |
title_full_unstemmed |
Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site |
title_sort |
interleukin-1β drives nedd8 nuclear-to-cytoplasmic translocation, fostering parkin activation via nedd8 binding to the p-ubiquitin activating site |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-12-01 |
description |
Abstract Background Neuroinflammation, typified by elevated levels of interleukin-1 (IL-1) α and β, and deficits in proteostasis, characterized by accumulation of polyubiquitinated proteins and other aggregates, are associated with neurodegenerative disease independently and through interactions of the two phenomena. We investigated the influence of IL-1β on ubiquitination via its impact on activation of the E3 ligase parkin by either phosphorylated ubiquitin (P-Ub) or NEDD8. Methods Immunohistochemistry and Proximity Ligation Assay were used to assess colocalization of parkin with P-tau or NEDD8 in hippocampus from Alzheimer patients (AD) and controls. IL-1β effects on PINK1, P-Ub, parkin, P-parkin, and GSK3β—as well as phosphorylation of parkin by GSK3β—were assessed in cell cultures by western immunoblot, using two inhibitors and siRNA knockdown to suppress GSK3β. Computer modeling characterized the binding and the effects of P-Ub and NEDD8 on parkin. IL-1α, IL-1β, and parkin gene expression was assessed by RT-PCR in brains of 2- and 17-month-old PD-APP mice and wild-type littermates. Results IL-1α, IL-1β, and parkin mRNA levels were higher in PD-APP mice compared with wild-type littermates, and IL-1α-laden glia surrounded parkin- and P-tau-laden neurons in human AD. Such neurons showed a nuclear-to-cytoplasmic translocation of NEDD8 that was mimicked in IL-1β-treated primary neuronal cultures. These cultures also showed higher parkin levels and GSK3β-induced parkin phosphorylation; PINK1 levels were suppressed. In silico simulation predicted that binding of either P-Ub or NEDD8 at a singular position on parkin opens the UBL domain, exposing Ser65 for parkin activation. Conclusions The promotion of parkin- and NEDD8-mediated ubiquitination by IL-1β is consistent with an acute neuroprotective role. However, accumulations of P-tau and P-Ub and other elements of proteostasis, such as translocated NEDD8, in AD and in response to IL-1β suggest either over-stimulation or a proteostatic failure that may result from chronic IL-1β elevation, easily envisioned considering its early induction in Down’s syndrome and mild cognitive impairment. The findings further link autophagy and neuroinflammation, two important aspects of AD pathogenesis, which have previously been only loosely related. |
topic |
IL-1β GSK3β PINK1 Alzheimer’s Parkin NEDD8 |
url |
https://doi.org/10.1186/s12974-019-1669-z |
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