Makorin Ring Finger Protein Research Articles

MKRN3 circulating levels in Prader-Willi syndrome: a pilot study.

Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6years. MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

Recent advances on the relationship between the delta-like noncanonical Notch ligand 1 system and central precocious puberty†.

Precocious puberty, as a common pediatric endocrine disease, can be divided into central precocious puberty and peripheral precocious puberty, even though most cases of precocious puberty are diagnosed as central precocious puberty. According to its etiology, central precocious puberty can be further divided into organic and idiopathic central precocious puberty. However, the mechanisms of idiopathic central precocious puberty have not yet been fully elucidated. Currently, four genes, including the kisspeptin gene, the kisspeptin receptor gene, the makorin ring finger protein 3, and the delta-like noncanonical Notch ligand 1, have been implicated in central precocious puberty cases, of which delta-like noncanonical Notch ligand 1 has been determined to represent a key, recently found central precocious puberty-related gene. In this review, we will not only highlight the latest discoveries on the relationship between the delta-like noncanonical Notch ligand 1 system and central precocious puberty but also explore the involvement of the system as well as the Notch signaling pathway in central precocious puberty occurrence.

Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response.

Mycobacterium tuberculosis (Mtb), as an important intracellular pathogen, can invade and survive in macrophages and is capable of escaping the clearance of immune system. Despite decades of research efforts, the precise mechanism of immune escape and the virulence factors encoded by Mtb involved remain to be explored. Mtb-specific genomic regions of deletion (RD)-encoded proteins and PE/PPE family proteins have been implicated in immune evasion. Here, we screened more than forty RD-encoded proteins which might be involved in facilitating bacterial survival in macrophages, and found that a Mtb PPE68/Rv3873 protein, encoded by Mtb-RD1, is essential for efficient Mtb intracellular survival in macrophages. In terms of mechanism, we found that the ubiquitin ligase (E3) Makorin Ring Finger Protein 1 (MKRN1) of macrophage interacted with PPE68 and promoted the attachment of lysine (K)-63-linked ubiquitin chains to the K166 site of PPE68. K63-ubiquitination of PPE68 further bound src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) to suppress K63-linked polyubiquitin chains of tumor necrosis factor receptor-associated factor 6 (TRAF6), and then remarkably suppressed TRAF6-driven NF-κB and AP-1 signaling and TNF-α, IL-6 and NO production. We demonstrate that the K63-linked ubiquitination of PPE68 by MKRN1 contributed to the PPE68-mediated mycobacterial immune escape. Our finding identifies a previously unrecognized mechanism by which host MKRN1-mediated-ubiquitination of mycobacterial PPE protein suppresses innate immune responses. Disturbing the interaction between host MKRN1 ubiquitin system and mycobacterial PPE protein might be a potential therapeutic target for tuberculosis.

MRKNs: Gene, Functions, and Role in Disease and Infection.

The makorin RING finger protein (MKRN) gene family encodes proteins (makorins) with a characteristic array of zinc-finger motifs present in a wide array from invertebrates to vertebrates. MKRNs (MKRN1, MKRN2, MKRN3, MKRN4) as RING finger E3 ligases that mediate substrate degradation are related with conserved RING finger domains that control multiple cellular components via the ubiquitin-proteasome system (UPS), including p53, p21, FADD, PTEN, p65, Nptx1, GLK, and some viral or bacterial proteins. MKRNs also served as diverse roles in disease, like MKRN1 in transcription regulation, metabolic disorders, and tumors; MKRN2 in testis physiology, neurogenesis, apoptosis, and mutation of MKRN2 regulation signals transduction, inflammatory responses, melanoma, and neuroblastoma; MKRN3 in central precocious puberty (CPP) therapy; and MKRN4 firstly reported as a novel E3 ligase instead of a pseudogene to contribute to systemic lupus erythematosus (SLE). Here, we systematically review advances in the gene’s expression, function, and role of MKRNs orthologs in disease and pathogens infection. Further, MKRNs can be considered targets for the host’s innate intracellular antiviral defenses and disease therapy.

Puberdade precoce central familiar por inativação do gene MKRN3: relato de caso

Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis. The factors involved in central early puberty are still poorly understood. Recently, mutations in the makorin ring finger protein 3 (MKRN3) gene have been identified in familial cases. We report the case of two sisters with central precocious puberty. The diagnosis, carried out by molecular analysis, showed an inactivating mutation of the MKRN3 gene.

Hyperoside Ameliorates DSS-Induced Colitis through MKRN1-Mediated Regulation of PPARγ Signaling and Th17/Treg Balance.

Hyperoside (HYP), a naturally occurring flavonoid compound, exerts multiple biological functions including myocardial protection, antiredox, and anti-inflammatory activities. However, the role of HYP on inflammatory bowel disease (IBD) and the underlying mechanism need to be further established. Here, we show that HYP treatment profoundly alleviated dextran sulfate sodium-induced ulcerative colitis in mice, characterized by reduced pathological scores, preserved tissue integrity, suppressed colonic inflammation, and balanced Th17/Treg response. Mechanistically, HYP was shown to restrain the expression of the E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), which in turn promoted the ubiquitination and proteasomal degradation of peroxisome proliferator-activated receptor gamma (PPARγ), an essential regulator of Th17 and Treg differentiation. Consequently, HYP treatment enhanced PPARγ signaling and hence promoted Treg differentiation while suppressing Th17 cell development during colitis. Thus, our data indicate that HYP acts through the MKRN1/PPARγ axis to modulate the Th17/Treg axis and thereby confers protection against experimental colitis. The findings extend our understanding about HYP action and may provide a potential therapeutic target for IBD.

Elevated expression of MKRN3 in squamous cell carcinoma of the head and neck and its clinical significance

BackgroundSquamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported.MethodsThe Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quantify the MKRN3 mRNA expression levels in SCCHN; immunohistochemical staining or immunoblotting analyses were performed to detect MKRN3 protein expression. Kaplan–Meier plotter was used to assess the prognostic values of MKRN3 in terms of overall survival and disease-free survival. The expression differences based on various clinicopathological features were evaluated using subgroup analysis and forest map analysis. The regulatory mechanism of MKRN3 was further investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Subsequently, STRING was used to perform a co-expression and enrichment analysis for MKRN3. Homologous modeling, molecular docking, and western blot analyses were performed to investigate the relationship between MKRN3 and its potential target gene P53.ResultsMKRN3 was ectopically expressed between cancerous and noncancerous SCCHN tissues, and its expression level was tightly associated with high T classifications as well as advanced clinical stages. qPCR analysis revealed that MKRN3 was upregulated in the SCCHN cell line. Moreover, Kaplan–Meier and Cox regression analyses indicated that SCCHN patients with high MKRN3 expression had poorer prognosis and that MKRN3 was a potential prognostic marker for SCCHN. Using gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we determined that MKRN3 may be involved in the regulation of synthesis and metabolism and cell growth, death and motility, as well as cancer pathways associated with SCCHN progression. Mechanism investigation further revealed that P53, a potential target of MKRN3, may be involved in the SCCHN tumorigenesis mediated by MKRN3.ConclusionsWe performed a comprehensive evaluation of the clinical significance of MKRN3 and explored its underlying mechanisms. We concluded that MKRN3 represents a valuable predictive biomarker and potential therapeutic target in SCCHN.

Genetic factors in precocious puberty

Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors. Most cases of precocious puberty (PP) are diagnosed as central PP (CPP), defined as premature activation of the HPG axis. The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. Other genes, such as gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1), lin-28 homolog B (LIN28B), neuropeptide Y (NPYR), tachykinin 3 (TAC3), and tachykinin receptor 3 (TACR3), have been implicated in the progression of ICPP, although their relationships require elucidation. Environmental and socioeconomic factors may also be correlated with ICPP. In the progression of CPP, epigenetic factors such as DNA methylation, histone posttranslational modifications, and noncoding ribonucleic acids may mediate the relationship between genetic and environmental factors. CPP is correlated with short- and long-term adverse health outcomes, which forms the rationale for research focusing on understanding its genetic and nongenetic factors.

Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus

ObjectivesMAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is...

The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls.

ObjectiveTo evaluate the characteristics and significance of serum kisspeptin and makorin ring finger protein 3 (MKRN3) levels for the diagnosis of central precocious puberty (CPP) in girls.MethodThirty four individuals with CPP, 17 individuals with premature thelarche (PT), and 28 age-matched prepubertal girls as normal control (NC) were recruited in this case–control study. Physical measurements included BMI and tests for breast, bone, and sexual characteristics. Biochemical measurements included serum LH, FSH, estradiol, insulin-like growth factor-1, MKRN3, and kisspeptin. Blood samples were taken from individuals with CPP and PT before the gonadotrophin-releasing hormone stimulation test and at 30, 60, 90, and 120 min after injection with triptorelin.ResultsSerum kisspeptin levels were higher in the CPP group when compared to the NC group (P = 0.020), while serum MKRN3 levels were lower in the two groups (P = 0.028). There were no significant differences between the CPP and PT groups as well as the PT and NC groups (all, P > 0.05). The cut-off value of serum kisspeptin differentiating patients with CPP from those without CPP was 0.40 nmol/L, with 82.4% sensitivity and 57.1% specificity, while the cut-off value of serum MKRN3 was 0.33 pmol/L, with 79.4% sensitivity and 53.6% specificity. The area under the curves (AUCs) of both kisspeptin and MKRN3 for differentiating those girls with CPP from PT were less than 0.5.ConclusionsSerum levels of kisspeptin and MKRN3 may play an auxiliary role in predicting CPP. However, the two measurements were not able to differentiate girls with CPP from PT and prepubertal control. This study emphasizes the need to search for markers to simplify the accurate diagnosis of CPP in girls.

Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

КЛИНИЧЕСКАЯ И МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКАЯ ХАРАКТЕРИСТИКА 3 СЕМЕЙНЫХ СЛУЧАЕВ ГОНАДОТРОПИНЗАВИСИМОГО ПРЕЖДЕВРЕМЕННОГО ПОЛОВОГО РАЗВИТИЯ, ОБУСЛОВЛЕННОГО МУТАЦИЯМИ В ГЕНЕ MKRN3

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 ( MKRN3 ) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty.

There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans. To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period. A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39PT (21 boys/18 girls) (gestational age 31-37weeks), were included. Blood samples were taken at 7days (D7), 2months (M2), and 6months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured. Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations. Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.

Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation

Mutations in the human gene encoding the neuron-specific Eag1 voltage-gated K+ channel are associated with neurodevelopmental diseases, indicating an important role of Eag1 during brain development. A disease-causing Eag1 mutation is linked to decreased protein stability that involves enhanced protein degradation by the E3 ubiquitin ligase cullin 7 (CUL7). The general mechanisms governing protein homeostasis of plasma membrane- and endoplasmic reticulum (ER)-localized Eag1 K+ channels, however, remain unclear. By using yeast two-hybrid screening, we identified another E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), as a novel binding partner primarily interacting with the carboxyl-terminal region of Eag1. MKRN1 mainly interacts with ER-localized immature core-glycosylated, as well as nascent nonglycosylated, Eag1 proteins. MKRN1 promotes polyubiquitination and ER-associated proteasomal degradation of immature Eag1 proteins. Although both CUL7 and MKRN1 contribute to ER quality control of immature core-glycosylated Eag1 proteins, MKRN1, but not CUL7, associates with and promotes degradation of nascent, nonglycosylated Eag1 proteins at the ER. In direct contrast to the role of CUL7 in regulating both ER and peripheral quality controls of Eag1, MKRN1 is exclusively responsible for the early stage of Eag1 maturation at the ER. We further demonstrated that both CUL7 and MKRN1 contribute to protein quality control of additional disease-causing Eag1 mutants associated with defective protein homeostasis. Our data suggest that the presence of this dual ubiquitination system differentially maintains Eag1 protein homeostasis and may ensure efficient removal of disease-associated misfolded Eag1 mutant channels.

MKRN1 Ubiquitylates p21 to Protect against Intermittent Hypoxia-Induced Myocardial Apoptosis.

Although chronic intermittent hypoxia- (IH-) induced myocardial apoptosis is an established pathophysiological process resulting in a poor prognosis for patients with obstructive sleep apnea syndrome, its underlying mechanism remains unclear. This study is aimed at exploring the role of makorin ring finger protein 1 (MKRN1) in IH-induced myocardial apoptosis and elucidating its molecular activity. First, the GSE2271 dataset was downloaded from the Gene Expression Omnibus database to identify the differentially expressed genes. Then, an SD rat model of IH, together with rat cardiomyocyte H9C2 and human cardiomyocyte AC16 IH models, was constructed. TUNEL, Western blot, and immunohistochemistry assays were used to detect cell apoptosis. Dihydroethidium staining was conducted to analyze the concentration of reactive oxygen species. In addition, RT-qPCR, Western blot, and immunohistochemistry were performed to measure the expression levels of MKRN1 and p21. The direct interaction between MKRN1 and p21 was determined using coimmunoprecipitation and ubiquitination analysis. MKRN1 expression was found to be downregulated in IH rat myocardial tissues as well as in H9C2 and AC16 cells. Upregulated expression of MKRN1 in H9C2 and AC16 cells alleviated the IH-induced reactive oxygen species production and cell apoptosis. Mechanistically, MKRN1 promoted p21 protein ubiquitination and the proteasome pathway degradation to negatively regulate p21 expression. Thus, MKRN1 regulates p21 ubiquitination to prevent IH-induced myocardial apoptosis.

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty.

Makorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus. This study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression. In this case-control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits. Serum MKRN3 level decreased significantly in CPPpatients compared to controls (344.48±333.77 and 1295.21±780.80pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14±31.75ng/mL and 12.93±8.28ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involvedin the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.

GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes.

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

Makorin rings the kisspeptin bell to signal pubertal initiation.

The signals maintaining quiescence of the reproductive endocrine axis during childhood before its reawakening at puberty had been enigmatic. Studies in patients with abnormal puberty have illuminated the identity of the signals; kisspeptin has emerged as a major stimulator of puberty, and makorin RING finger protein 3 (MKRN3) as an inhibitory signal that prevents premature initiation of puberty. In this issue of the JCI, Abreu et al. investigated the mechanism by which MKRN3 regulates pubertal onset. The authors found that a reduction in MKRN3 alleviated the constraint on kisspeptin-expressing neurons to allow pubertal initiation, a phenomenon observed across species, including nonhuman primates. Further, the ubiquitinase activity of MKRN3 required its RING finger domain, in order to repress the promoter activity of genes encoding kisspeptin and neurokinin B. These data advance our understanding of the regulation of kisspeptin-expressing neurons by MKRN3 to initiate puberty.

Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells

Neuroblastoma (NB) is a paediatric tumour that shows great biomolecule and clinical heterogeneity, and patients with NB often develop various neurological complications. Currently, the disease is mainly treated by surgery and still lacks specific therapeutic drugs; therefore, targets are urgently needed. Makorin ring finger protein 2 (MKRN2) is an E3 ligase whose effects on neuroblastoma have not been illustrated. shRNAs for MKRN2 have been designed, and MKRN2-knockdown human neuroblastoma SHSY5Y cells were established. MKRN2 knockdown promotes the proliferation and migration of SHSY5Y cells. Because MKRN2 is an E3 ligase, we performed a series of experiments, and Insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) was identified as a new substrate for MKRN2. IGF2BP3 is an RNA-binding protein that regulates the stability of many mRNAs, including CD44 and PDPN, and our study demonstrated that MKRN2 regulates the expression of CD44 and PDPN in an IGF2BP3-dependent manner. These results suggest that MKRN2 might be a potential therapeutic target for neuroblastoma.