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Int. J. Mol. Sci. 2017, 18(4), 835; doi:10.3390/ijms18040835

SAK-HV Decreases the Self-Ubiquitination of MEKK1 to Promote Macrophage Proliferation via MAPK/ERK and JNK Pathways

The Laboratory of Genomic Engineering, Beijing Institute of Basic Medical Sciences, Beijing 100005, China
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Academic Editor: Nobuhiro Nakamura
Received: 9 February 2017 / Revised: 6 April 2017 / Accepted: 11 April 2017 / Published: 19 April 2017
(This article belongs to the Special Issue Ubiquitin System)
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Abstract

SAK-HV is an anti-atherosclerosis recombinant fusion protein developed by our lab. Our study determined that SAK-HV promoted macrophage proliferation, of which the mechanism was explored by both RAW264.7 cells and primary macrophages. Mass spectrometric analysis and co-immunoprecipitation were combined to screen the SAK-HV-interacting proteins in RAW264.7 cells. Confocal microscopy was adopted to detect the localization of SAK-HV in cells. The results indicated that SAK-HV triggered macrophage proliferation via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) pathways by its SAK-mutant functional domain. We screened out Uba1 as the SAK-HV-interacting protein in the RAW264.7 cells and discovered their co-localization in the cytoplasm and nucleus. Inhibiting Uba1 significantly decreased the SAK-HV-induced macrophage proliferation. Thus, we postulated an attractive model of ubiquitination, in which the interactions between Uba1 and specific E2 enzymes are blocked by its interaction with SAK-HV. Based on this model, we detected the decreased self-ubiquitination of MEKK1 after SAK-HV treatment and concluded that SAK-HV inhibits the self-ubiquitination of MEKK1 via its SAK-mutant functional domain to activate MAPK/ERK and JNK pathways, promoting macrophage proliferation. This conclusion highly supported our hypothesized model of ubiquitination at the level of Uba1, which may represent a novel paradigm to promote macrophage proliferation by using the E1 enzyme (Uba1) as a switch. View Full-Text
Keywords: macrophage proliferation; ubiquitination; Uba1; MEKK1; ERK; JNK macrophage proliferation; ubiquitination; Uba1; MEKK1; ERK; JNK
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MDPI and ACS Style

Zhang, C.; Chen, Y.; Gan, X.; Huang, Z.; Zou, M.; Fu, W.; Xing, W.; Xu, D. SAK-HV Decreases the Self-Ubiquitination of MEKK1 to Promote Macrophage Proliferation via MAPK/ERK and JNK Pathways. Int. J. Mol. Sci. 2017, 18, 835.

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