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Review
. 2023 Apr 25;11(2):687-700.
doi: 10.1016/j.gendis.2023.03.021. eCollection 2024 Mar.

The journey towards physiology and pathology: Tracing the path of neuregulin 4

Min Chen  1 , Jieying Zhu  1 , Hongyang Luo  1 , Wangjing Mu  1 , Liang Guo  1
Affiliations
Review

The journey towards physiology and pathology: Tracing the path of neuregulin 4

Min Chen et al. Genes Dis. .

Abstract

Neuregulin 4 (Nrg4), an epidermal growth factor (EGF) family member, can bind to and activate the ErbB4 receptor tyrosine kinase. Nrg4 has five different isoforms by alternative splicing and performs a wide variety of functions. Nrg4 is involved in a spectrum of physiological processes including neurobiogenesis, lipid metabolism, glucose metabolism, thermogenesis, and angiogenesis. In pathological processes, Nrg4 inhibits inflammatory factor levels and suppresses apoptosis in inflammatory diseases. In addition, Nrg4 could ameliorate obesity, insulin resistance, and cardiovascular diseases. Furthermore, Nrg4 improves non-alcoholic fatty liver disease (NAFLD) by promoting autophagy, improving lipid metabolism, and inhibiting cell death of hepatocytes. Besides, Nrg4 is closely related to the development of cancer, hyperthyroidism, and some other diseases. Therefore, elucidation of the functional role and mechanisms of Nrg4 will provide a clearer view of the therapeutic potential and possible risks of Nrg4.

Keywords: Angiogenesis; Cardiovascular diseases; Inflammation; Insulin resistance; Lipid and glucose metabolism; NAFLD; Neurobiogenesis; Obesity.

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Figures

Fig. 1
Figure 1
The variants of Nrg4 gene and the sequence alignment of Nrg4 proteins among species. (A) The human Nrg4 gene encodes five different isoforms, namely A1, A2, B1, B2, and B3. These isoforms are the result of alternative splicing of exons 1–9 of Nrg4 gene, and all isoforms contain exons 1 and 2. Both Nrg4 A1 and A2 encode a complete epidermal growth factor (EGF) like region (containing codon encoding a glycosylation site) and transmembrane domain (exon 2 and exon 6). The difference is that the cytoplasmic tails of Nrg4 A1 and A2 are encoded by different exons (exons 8 and 9 for A1, and exon 7 for A2). Furthermore, Nrg4 B1 is spliced from exon 2 into exon 5 and Nrg4 B2 is spliced from exon 2 into exon 4, prior to the stop codon. Nrg4 B3 is spliced from exon 2 into exon 3, and exon 3 contains a codon encoding a predicted nonreceptor tyrosine kinase (NRTK) phosphorylation site. (B) Comparison of Nrg4 A1 protein sequences of human, mouse, cat, pig, and chicken. Among the 5 sequences, 3, 4, and 5 identical amino acids are represented in green, pink, and dark blue, respectively. A homology of 85.17% is detected among the Nrg4 proteins of different species.
Fig. 2
Figure 2
The Nrg4 receptor ERBB4 has different variants and mediates different signal transduction. (A) ErbB4 has four different isoforms, all of which can recognize Nrg4. ErbB4 isoforms are different in their extracellular domain near the juxtamembrane (JM) or in the cytoplasmic region near the C-terminal. The JM isoforms differ by having a 23-amino acid (JM-a) or 13-amino acid (JM-b) inserted. JM-a contains the tumor necrosis factor-α-converting enzyme (TACE) site. Activated ERBB4 is first cleaved within the JM region through the activity of TACE. The TACE-processed ErbB4 is then cleaved by γ-secretase, leading to the release of the intracellular domain (ICD) from cellular membranes. ErbB4 ICD is able to play a functional role in the cytoplasm and nucleus. The cytoplasmic (CYT) variants differ by having (CYT-1) or not having (CYT-2) a 16-amino acid insert in the cytoplasmic tail. CYT-1 contains the 16 amino acids, which form a binding site for PI3K, while CYT-2 lacks the 16 amino acids. All ErbB4 variants contain shell script compiler (Shc) binding sites in the cytoplasmic region. (B) The EGF-like motif of Nrg4 can be cleaved and released, and then recognize and activate ErbB4, which in turn triggers signal transduction. Nrg4-mediated activation of ErbB4 can stimulate PI3K/AKT signaling pathway. Activated ErbB4 can couple with shell script compiler (Shc), and Shc in turn activates the mitogen-activated protein kinase (MAPK) (Erk-1 and Erk-2) signaling pathway. Moreover, the ICD of ErbB4 accumulated in the nucleus directly regulates the function of signal transducer and activator of transcription 5 a (STAT5a) in the transcriptional regulation of target genes. In addition, ErbB4 can combine with itself to form a homodimer, or it can recruit ErbB1, ErbB2, or ErbB3 to form heterodimers.
Fig. 3
Figure 3
Nrg4 is involved in a spectrum of physiological processes including lipid metabolism, glucose metabolism, neurobiogenesis, angiogenesis, and thermogenesis. In lipid metabolism, Nrg4 can promote the phosphorylation of STAT5 significantly to repress the transcriptional activity of the liver-X receptor (LXR), leading to cell-autonomous repressed expression of the sterol regulatory element binding transcription factor 1 (Srebf1), acetyl coenzyme A carboxylase (Acaca), stearoyl-CoA desaturase 1 (Scd1), and fatty acid synthase (Fasn) in hepatocytes. In glucose metabolism, Nrg4/ErbB4 signaling may promote glucose uptake by increasing glucose transporter 4 (Glut4) redistribution to the plasma membrane. Moreover, Nrg4 can promote AKT/PKB phosphorylation to increase the uptake of glucose in 3T3-L1 adipocytes. In addition, Nrg4 increases the activity of the mammalian target of rapamycin complex 1 (mTORc1) and decreases the expression of autophagy marker microtubule-associated protein light chain 3B form II (LC3B-II), which can block Glut4 storage vesicle (GSV) degradation by autophagy in adipocytes. In neurobiogenesis, Nrg4 can promote the growth of axons and dendrites of neurons, and increase the length and complexity of dendrites. In angiogenesis, Nrg4 overexpression resulted in increased vascular density in adipose tissue. In thermogenesis, Nrg4 is able to stimulate the expression of thermogenic genes in BAT, including Ucp1, Ucp3, Cidea, and Dio2, and Nrg4 can promote the expression of beige fat markers PAT2 and CD137.
Fig. 4
Figure 4
The effects of Nrg4 on inflammatory diseases, obesity, insulin resistance, diabetes, and cardiovascular diseases. (A) In inflammatory bowel disease, Nrg4 can activate PI3K/AKT signaling pathway, which in turn promotes colonic epithelial cell survival. In addition, Nrg4 can promote M1 macrophage apoptosis through ErbB4 ICD binding to mitochondria, which reduces the production of TNFα, Cxcl1, and IL-1β from macrophages. (B) In osteoarthritis, Nrg4 inhibits the activation of JNK phosphorylation and reduces chondrocyte apoptosis. Moreover, Nrg4-mediated inhibition of JNK signaling also results in the reduction of the matrix metalloproteinase 13 (MMP-13), an enzyme for the degradation of type II collagen (COL II), thereby inhibiting the degradation of COL II in chondrocytes. (C) Nrg4 may have an anti-obesity effect. In addition, Nrg4 can increase Glut4 levels on the plasma membranes to promote glucose transport and uptake in 3T3-L1 adipocytes. Nrg4 suppresses the activation of the transcription factor NF-κB and the expression of its downstream inflammatory factors (including TNFα, IL-1β, IL-6, and IFNβ) in 3T3-L1 adipocytes. Besides, Nrg4/ErbB4 signaling leads to increased adipose tissue angiogenesis to improve adipose tissue function and preserve metabolic health. These effects above help to ameliorate insulin resistance. The beneficial role of Nrg4 in diabetes needs further exploration. In cardiovascular disease, BAT-derived Nrg4 activates Akt signaling through ErbB4 receptor, which inhibits the NF-κB activity to reduce endothelial inflammation and injury, thereby ameliorating atherosclerosis. In addition, the levels of circulating Nrg4 were significantly elevated after exercise, suggesting the potential roles of Nrg4 in exercise-mediated metabolic health.
Fig. 5
Figure 5
The potential roles of Nrg4 in NAFLD, cancer, and thyroid disorders. (A) Nrg4 has a protective role against non-alcoholic fatty liver disease (NAFLD). In hepatocytes, Nrg4 may induce autophagy through the activation of AMPK signaling and the inhibition of mTOR signaling. This in turn attenuates hepatic steatosis in aged mice. Nrg4/ErbB4 signaling can increase phosphorylation of endogenous ErbB3 and STAT5 proteins, and activated STAT5 inhibits LXR transcriptional activity, which inhibits the expression of Srebf1, the gene encoding Srebp-1c that promotes lipogenesis. Moreover, Nrg4 inhibits the expression of PPARγ and its target genes (Cd36, Mgat1, and Fabp4) in the liver, thus preventing hepatic steatosis. Nrg4 is able to suppress the expression of lipogenic genes (Srebf1, Acaca, Fasn, and Scd1) in the liver. Whether Nrg4 could ameliorate NAFLD by promoting fatty acid β-oxidation needs further investigation. Furthermore, Nrg4 can inhibit the JNK1/2 phosphorylation by activating AKT and then reduces the ubiquitination and proteosomal degradation of FADD-like apoptosis regulator (c-FLIPL) to exert cytoprotective effects, which hinders the development of hepatic steatosis to NASH. (B) Nrg4 is shown to play potential roles in cancer, thyroid disorders, diabetic nephropathy, and polycystic ovary syndrome. In cancer, Nrg4 is highly expressed in melanoma, prostate cancer, and malignant lymphoma in the gastrointestinal tract, and it can promote the proliferation of the above cancer cells. However, Nrg4 is down-regulated in a mouse model of NASH-related hepatocellular carcinoma (HCC). Nrg4 can inhibit NASH-related HCC by impairing tumor-prone liver immune microenvironment. In addition, Nrg4 and its receptor ErbB4 were significantly reduced in cancerous tissues from patients with bladder cancer and gastric cancer. The exact roles of Nrg4 in different cancers need further exploration. In thyroid disorders, Nrg4 levels were positively correlated with serum-free T3, free T4, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) levels, but negatively correlated with thyroid stimulating hormones (TSH). In diabetic nephropathy, Nrg4 can attenuate renal function injury, tubulointerstitial fibrosis, inflammation and suppress the expression levels of advanced glycosylation end products (AGEs). In polycystic ovary syndrome, serum Nrg4 levels are significantly elevated in patients with polycystic ovary syndrome, and the role and mechanism of Nrg4 in polycystic ovary syndrome need to be further explored.
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