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NADPH oxidase (NOX)-derived oxidative stress is an important factor in renal progression, with NOX4 being the predominant NOX in the kidney. Recently, Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1) was reported to be a regulator of NOX4. In this study, we tested whether the SH3YL1 protein could predict 3-year renal outcomes in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were enrolled in this study. Renal events were defined as a 15% decline in the estimated glomerular filtration rate (eGFR) from the baseline, the initiation of renal replacement therapy, or death during the 3 years. The levels of the urinary SH3YL1-to-creatinine ratio (USCR) were significantly different among the five stages of chronic kidney disease (CKD) and the three groups, based on albuminuria levels. The USCR levels showed a significant negative correlation with eGFR and a positive correlation with the urinary albumin-to-creatinine ratio (UACR). Plasma SH3YL1 levels were significantly correlated with UACR. The highest tertile group of USCR and plasma SH3YL1 had a significantly lower probability of renal event-free survival. Furthermore, the highest tertile group of USCR showed a significant association with the incidence of renal events after full adjustment: adjusted hazard ratio (4.636: 95% confidence interval, 1.416–15.181, p = 0.011). This study suggests that SH3YL1 is a new diagnostic biomarker for renal outcomes in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The goal of this study was to explore the association between Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein and diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM). The study included 90 participants, 60 patients with T2DM all recruited from Outpatients Clinic and Internal Medicine Inpatient Department, Beni-Suef University Hospital; and 30 apparently healthy controls. Patients were sub-divided into group I: 20 patients with no albuminuria, group II: 20 patients with microalbuminuria and group III: 20 patients with macroalbuminuria. All participants were subjected to full history taking, routine laboratory investigations and serum SH3YL1 analysis using enzyme-linked immunosorbent (ELISA) assay. Serum SH3YL1 was significantly higher in T2DM patients (5.69 ± 1.6 ng/ml) versus controls (3.76 ±0.80 ng/ml) (p

There is growing evidence that NADPH oxidase 4 (Nox4) in hepatocytes contributes to liver inflammation and fibrosis during the development of metabolic dysfunction-associated steatohepatitis (MASH). However, how Nox4 is regulated and leads to liver pathogenesis is unclear. Our previous studies showed that the cytosolic protein SH3 domain-containing Ysc84-like 1 (SH3YL1) regulates Nox4 activity. Here, we asked whether SH3YL1 also participates in liver inflammation and fibrosis during MASH development. We generated that whole body SH3YL1 knockout (SH3YL1 -/- ), Nox4 knockout (Nox4 -/- ) mice, and the hepatocyte-specific SH3YL1 conditional knockout (Alb-Cre/SH3YL1 fl/fl ) mice were fed a methionine/choline-deficient (MCD) diet to induce liver inflammation and fibrosis in pathogenesis of MASH. Palmitate-stimulated primary SH3YL1-and Nox4-deficient hepatocytes and hepatic stellate cells (HSCs) did not generate H 2 O 2 . While the liver of MCD diet-fed wild type (WT) mice demonstrated elevated 3-nitrotyrosine as a protein oxidation and 4-hydroxynonenal adducts as a lipid oxidation and increased liver inflammation, hepatocyte apoptosis, and liver fibrosis, these events were markedly reduced in SH3YL1 -/- , Nox4 -/- , and Alb-Cre/SH3YL1 fl/fl mice. The MCD diet-fed WT mice also showed elevated hepatocyte expression of SH3YL1 protein. Similarly, liver biopsies from MASH patients demonstrated strong hepatocyte SH3YL1 protein expression, whereas hepatocytes from patients with steatosis weakly expressed SH3YL1 and histologically normal patient hepatocytes exhibited very little SH3YL1 expression. The Nox4-SH3YL1 complex in murine hepatocytes elevates their H 2 O 2 production, which promotes the liver inflammation, hepatocyte apoptosis, and liver fibrosis that characterize MASH. This axis may also participate in MASH in humans., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

NADPH oxidase (NOX)-derived oxidative stress is an important factor in renal progression, with NOX4 being the predominant NOX in the kidney. Recently, Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1) was reported to be a regulator of NOX4. In this study, we tested whether the SH3YL1 protein could predict 3-year renal outcomes in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were enrolled in this study. Renal events were defined as a 15% decline in the estimated glomerular filtration rate (eGFR) from the baseline, the initiation of renal replacement therapy, or death during the 3 years. The levels of the urinary SH3YL1-to-creatinine ratio (USCR) were significantly different among the five stages of chronic kidney disease (CKD) and the three groups, based on albuminuria levels. The USCR levels showed a significant negative correlation with eGFR and a positive correlation with the urinary albumin-to-creatinine ratio (UACR). Plasma SH3YL1 levels were significantly correlated with UACR. The highest tertile group of USCR and plasma SH3YL1 had a significantly lower probability of renal event-free survival. Furthermore, the highest tertile group of USCR showed a significant association with the incidence of renal events after full adjustment: adjusted hazard ratio (4.636: 95% confidence interval, 1.416–15.181, p = 0.011). This study suggests that SH3YL1 is a new diagnostic biomarker for renal outcomes in patients with type 2 diabetes.

Background and Aims: Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy.Methods and Results: In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis.Conclusion: These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Summary: Cytosolic proteins are required for regulation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) isozymes. Here we show that Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1), as a Nox4 cytosolic regulator, mediates lipopolysaccharide (LPS)-induced H2O2 generation, leading to acute kidney injury. The SH3YL1, Ysc84p/Lsb4p, Lsb3p, and plant FYVE proteins (SYLF) region and SH3 domain of SH3YL1 contribute to formation of a complex with Nox4-p22phox. Interaction of p22phox with SH3YL1 is triggered by LPS, and the complex induces H2O2 generation and pro-inflammatory cytokine expression in mouse tubular epithelial cells. After LPS injection, SH3YL1 knockout mice show lower levels of acute kidney injury biomarkers, decreased secretion of pro-inflammatory cytokines, decreased infiltration of macrophages, and reduced tubular damage compared with wild-type (WT) mice. The results strongly suggest that SH3YL1 is involved in renal failure in LPS-induced acute kidney injury (AKI) mice. We demonstrate that formation of a ternary complex of p22phox-SH3YL1-Nox4, leading to H2O2 generation, induces severe renal failure in the LPS-induced AKI model.

Understanding how actin filaments are nucleated, polymerized and disassembled in close proximity to cell membranes is an area of growing interest. Protrusion of the plasma membrane is required for cell motility, whereas inward curvature or invagination is required for endocytic events. These morphological changes in membrane are often associated with rearrangements of actin, but how the many actin-binding proteins of eukaryotes function in a co-ordinated way to generate the required responses is still not well understood. Identification and analysis of proteins that function at the interface between the plasma membrane and actin-regulatory networks is central to increasing our knowledge of the mechanisms required to transduce the force of actin polymerization to changes in membrane morphology. The Ysc84/SH3yl1 proteins have not been extensively studied, but work in both yeast and mammalian cells indicate that these proteins function at the hub of networks integrating regulation of filamentous actin (F-actin) with changes in membrane morphology. [ABSTRACT FROM AUTHOR]

Background: Sh3yl1, which contains one Src homology (SH) 3 domain, has been previously identified from mouse skin and considered to play an important role in hair follicle formation by interacting with other proteins. Objective: We performed this study to identify proteins capable of associating with Sh3yl1. Methods: We screened a mouse skin cDNA library using the SH3 domain of Sh3yl1 as bait in the yeast two-hybrid system. Results: We identified a 420-amino acid-long protein containing a proline-rich stretch and five carboxyl-terminal SH3 domains, which we have termed Sh3d19. We confirmed the interactions between Sh3yl1 and Sh3d19 by in vitro binding assays. Northern blot analysis showed that Sh3d19 transcripts in mouse skin were expressed in accordance with the hair cycle. Furthermore, RNA in situ hybridization studies demonstrated that its transcripts were detected predominantly in the medulla cells at the level corresponding to the keratogenous zone of the hair follicles during the mid and late anagen phases. Conclusion: Sh3d19 is a novel adaptor protein that may be involved in the development of medulla cells during the anagen phase. [Copyright &y& Elsevier]

Cytosolic proteins are required for regulation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) isozymes. Here we show that Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1), as a Nox4 cytosolic regulator, mediates lipopolysaccharide (LPS)-induced H 2 O 2 generation, leading to acute kidney injury. The SH3YL1, Ysc84p/Lsb4p, Lsb3p, and plant FYVE proteins (SYLF) region and SH3 domain of SH3YL1 contribute to formation of a complex with Nox4-p22 phox . Interaction of p22 phox with SH3YL1 is triggered by LPS, and the complex induces H 2 O 2 generation and pro-inflammatory cytokine expression in mouse tubular epithelial cells. After LPS injection, SH3YL1 knockout mice show lower levels of acute kidney injury biomarkers, decreased secretion of pro-inflammatory cytokines, decreased infiltration of macrophages, and reduced tubular damage compared with wild-type (WT) mice. The results strongly suggest that SH3YL1 is involved in renal failure in LPS-induced acute kidney injury (AKI) mice. We demonstrate that formation of a ternary complex of p22 phox -SH3YL1-Nox4, leading to H 2 O 2 generation, induces severe renal failure in the LPS-induced AKI model., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Ubiquitinated membrane proteins such as epidermal growth factor receptor (EGFR) are delivered to early endosomes and then sorted to lysosomes via multivesicular bodies (MVBs) for degradation. The regulatory mechanism underlying formation of intralumenal vesicles en route to generation of MVBs is not fully understood. In this study, we found that SH3YL1, a phosphoinositide-binding protein, had a vesicular localization pattern overlapping with internalized EGF in endosomes in the degradative pathway. Deficiency of SH3YL1 prevents EGF trafficking from early to late endosomes and inhibits degradation of EGFR. Moreover, we show that SH3YL1 mediates EGFR sorting into MVBs in a manner dependent on its C-terminal SH3 domain, which is necessary for the interaction with an ESCRT-I component, Vps37B. Taken together, our observations reveal an indispensable role of SH3YL1 in MVB sorting and EGFR degradation mediated by ESCRT complexes., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)