The E3 ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) promotes M2 macrophage polarization by ubiquitinating and activating transcription factor CCAAT/enhancer-binding Protein β (C/EBPβ)
Authors: Jing Jin
Mingjin Yang
Yizhi Yu
Hongmei Xu
Chunmei Wang
Xuetao Cao
Shuo Ye
Journal: Journal of Biological Chemistry (2012)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Macrophage activation; M1; M2; Ubiquitination; Arginase 1
Affiliations: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.

Abstract:  Macrophage activation, including classical (M1) activation and alternative (M2) activation, plays important roles in host immune response and pathogenesis of diseases. Ubiquitination has been shown to be involved in the differentiation of immune cells and in the regulation of immune responses. However, the role of ubiquitination during M1 versus M2 polarization is poorly explored. Here, we showed that arginase 1 (Arg1), a well recognized marker of M2 macrophages, is highly up-regulated in peritoneal macrophages derived from E3 ubiquitin ligase Nrdp1 transgenic (Nrdp1-TG) mice. Furthermore, other M2 feature markers such as MR, Ym1, and Fizz1, as well as Th2 cytokine IL-10, are also up-regulated in Nrdp1-TG macrophages after IL-4 stimulation. Knockdown of Nrdp1 expression effectively inhibits IL-4-induced expression of M2-related genes in macrophages. Moreover, Nrdp1 inhibits LPS-induced production of inducible NOS and pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in macrophages. Immunoprecipitation assays show that Nrdp1 interacts with and ubiquitinates transcriptional factor C/EBPβ via Lys-63-linked ubiquitination. Nrdp1 enhances C/EBPβ-triggered transcriptional activation of the Arg1 reporter gene in the presence of IL-4 stimulation. Thus, we demonstrate that Nrdp1-mediated ubiquitination and activation of C/EBPβ contributes to a ubiquitin-dependent nonproteolytic pathway that up-regulates Arg1 expression and promotes M2 macrophage polarization. 

Retracted: No

PubPeer comments:
 2020 Expression of Concern. https: www.jbc.org content 295 26 8884 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 Retraction on Jan 1, 2021, published online May 19, 2021 https: www.jbc.org article S0021-9258(21)00548-2 fulltext Withdrawal: The E3 ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) promotes M2 macrophage polarization by ubiquitinating and activating transcription factor CCAAT enhancer-binding protein u03b2 (C EBPu03b2) This article has been withdrawn by the authors. The Journal states that the Nrdp1 immunoblots in Figs. 1C and 3A were identical, flipped horizontally. In Fig. 2A the bands in lanes 1 and 4, corresponding to actin, were also duplicated. The first and last lanes of the C EBPu03b2 immunoblot in Fig. 5A (left) were reused in Fig. 5C as the second and third lane of the C EBPu03b2 immunoblot (left). The Nrdp1 immunoblot in Fig. 5A (left) was reused as STAT6 with a horizontal flip in Fig. 5C (right). The authors state that they disagree with the Journalu2019s findings. For 1C and 3A, the authors also provide supportive materials and offer to update the published record with images from experiments under the same conditions. The Journal declined the offer. This study was conducted more than 10 years ago. The age of the work and the lack of availability of data storage makes it difficult for the authors to retrieve some of the requested raw data. The authors state that the above issues do not affect the interpretation of the data nor conclusions of this research study. The authors have indicated that they plan to resubmit their findings elsewhere for publication. ,