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)

Ye, Shuo; Xu, Hongmei; Jin, Jing; Yang, Mingjin; Wang, Chunmei; Yu, Yizhi; Cao, Xuetao

doi:10.1074/jbc.m112.383265

Cited by 37 publications

(30 citation statements)

References 41 publications

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“…The M2 program was reported to be specifically sensitive to C/EBP levels (28). An E3 ligase, Nrdp1, was reported to K-63 ubiquitinate C/EBPβ and activate it to enhance transcription of Arg1 in Il-4-polarized macrophages (35). In the macrophages of transgenic mice expressing Nrdp1, not only Arg 1 but also other M2 markers such as YM1, FIZZ1, and IL-10 were upregulated.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors STAT6 and KLF4 Implement Macrophage Polarization via the Dual Catalytic Powers of MCPIP

Kapoor

Niu

Saad

et al. 2015

The Journal of Immunology

150

123

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Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCPIP, induced by KLF4, inhibits M1 polarization by inhibiting NF-κB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress and autophagy required for M2 polarization. MCPIP also induces C/EBPβ and PPARγ that promote M2 polarization. Macrophages from mice with myeloid-targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP.

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Section: Discussionmentioning

confidence: 99%

Transcription Factors STAT6 and KLF4 Implement Macrophage Polarization via the Dual Catalytic Powers of MCPIP

Kapoor

Niu

Saad

et al. 2015

The Journal of Immunology

150

123

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“…In addition to its impact on ErbB3, Nrdp1 is believed to mediate the ubiquitination of several other proteins including ErbB4 (17), several type 1 cytokine receptors (38 -40), the Toll-like receptor signaling adapter protein MyD88 (41), the inhibitor of apoptosis domain-containing protein BRUCE (42), the nuclear factors retinoic acid receptor (38) and C/EBP␤ (43), and the E3 ligase Parkin (44). This breadth of substrates targeted by Nrdp1 suggests that the ligase is a key regulator of critical signaling proteins and gives Nrdp1 potential roles in prostate cancer (45), cardiac disease (46,47), and Parkinson disease (44) in addition to breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Oligomerization of the Nrdp1 E3 Ubiquitin Ligase Is Necessary for Efficient Autoubiquitination but Not ErbB3 Ubiquitination

Printsev¹,

Yen

Sweeney

et al. 2014

Journal of Biological Chemistry

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Background: Nrdp1 ubiquitinates itself and ErbB3 to facilitate the degradation of both proteins. Result: Coiled-coil domain deletion abrogates Nrdp1 oligomerization and suppresses Nrdp1 but not ErbB3 ubiquitination and degradation. Conclusion: Oligomerization is required for efficient Nrdp1-mediated autoubiquitination but not ErbB3 ubiquitination. Significance: Nrdp1 autoubiquitination and substrate ubiquitination may be functionally separated, allowing a novel treatment strategy for breast cancer patients.

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“…In addition to ErbB3 and ErbB4 (12, 61), Nrdp1 has been reported to promote the ubiquitination and degradation of a diverse array of proteins involved in cellular regulation, including several type 1 cytokine receptors (62–64), the Toll-like receptor signaling adapter protein MyD88 (65), the inhibitor of apoptosis domain–containing protein BRUCE (66), the nuclear factors retinoic acid receptor (62) and C/EBPb (67), and the E3 ubiquitin ligase Parkin (68). Moreover, as a regulator of the stability of key signaling proteins, Nrdp1 could play roles in the onset or progression of various disease states that involve ER and cellular stresses, including breast cancer (38, 69, 70), prostate cancer (60, 71), colorectal cancer (72–74), glioblastoma (75, 76), cardiac disease (77, 78), Parkinson’s disease (68), and diabetes (59, 79).…”

Section: Discussionmentioning

confidence: 99%

The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3

et al. 2016

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ErbB3 and ErbB4 are receptor tyrosine kinases that are activated by the neuregulin (NRG) family of growth factors. These receptors govern various developmental processes, and their dysregulation contributes to several human disease states. The abundance of ErbB3 and ErbB4, and thus signaling through these receptors, is limited by the E3 ubiquitin ligase Nrdp1, which targets ErbB3 and ErbB4 for degradation. Reticulons are proteins that influence the morphology of the endoplasmic reticulum (ER) by promoting the formation of tubules, a response of cells to some stressors. We found that the ER structural protein reticulon 4A (Rtn4A, also known as Nogo-A) increased ErbB3 abundance and proliferative signaling by suppressing Nrdp1 function. Rtn4A interacted with Nrdp1 and stabilized ErbB3 in an Nrdp1-dependent manner. Rtn4A overexpression induced the redistribution of Nrdp1 from a cytosolic or perinuclear localization to ER tubules. Rtn4A knockdown in human breast tumor cells decreased ErbB3 abundance, NRG-stimulated signaling, and cellular proliferation and migration. Because proteins destined for the plasma membrane are primarily synthesized in the sheet portions of the ER, our observations suggest that Rtn4A counteracts the Nrdp1-mediated degradation of ErbB3 by sequestering the ubiquitin ligase into ER tubules. The involvement of a reticulon suggests a molecular link between ER structure and the sensitivity of cells to receptor tyrosine kinase–mediated survival signals at the cell surface.

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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)

Cited by 37 publications

References 41 publications

Transcription Factors STAT6 and KLF4 Implement Macrophage Polarization via the Dual Catalytic Powers of MCPIP

Transcription Factors STAT6 and KLF4 Implement Macrophage Polarization via the Dual Catalytic Powers of MCPIP

Oligomerization of the Nrdp1 E3 Ubiquitin Ligase Is Necessary for Efficient Autoubiquitination but Not ErbB3 Ubiquitination

The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3

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