The E3 ubiquitin ligase NEDD4-1 protects against acetaminophen-induced liver injury by targeting VDAC1 for degradation

Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.

NEDD4-1 deficiency impairs satellite cell function during skeletal muscle regeneration

BACKGROUND: Satellite cells are tissue-specific stem cells primarily responsible for the regenerative capacity of skeletal muscle. Satellite cell function and maintenance are regulated by extrinsic and intrinsic mechanisms, including the ubiquitin-proteasome system, which is key for maintaining protein homeostasis. In this context, it has been shown that ubiquitin-ligase NEDD4-1 targets the transcription factor PAX7 for proteasome-dependent degradation, promoting muscle differentiation in vitro. Nonetheless, whether NEDD4-1 is required for satellite cell function in regenerating muscle remains to be determined. RESULTS: Using conditional gene ablation, we show that NEDD4-1 loss, specifically in the satellite cell population, impairs muscle regeneration resulting in a significant reduction of whole-muscle size. At the cellular level, NEDD4-1-null muscle progenitors exhibit a significant decrease in the ability to proliferate and differentiate, contributing to the formation of myofibers with reduced diameter. CONCLUSIONS: These results indicate that NEDD4-1 expression is critical for proper muscle regeneration in vivo and suggest that it may control satellite cell function at multiple levels.

The Role of NEDD4-1 in Tumorigenesis of the Digestive System / 中国生物化学与分子生物学报

Neural precursor cell Expressed‚Developmentally Down-regulated protein 4 (NEDD4-1‚ also known as NEDD4 in some papers) is a tumor-related protein that has attracted much attention in recent years. It belongs to the E3 HECT (homologous to E6 associated protein C terminus) ubiquitin ligase‚ which could ubiquitinate various proteins that are subsequently degraded in lysosomes or proteasomes‚ or mediate their nuclear-cytoplasmic translocation‚ or indirectly affect various signaling pathways of different malignant tumors. With the deepening of a large number of tumor-related experiments‚ it has been found that NEDD4-1 can affect the biological behavior of tumors by regulating cell cycle‚ invasion and metastasis of cancer cells‚ antagonize drug resistance and many other pathways. In digestive system tumors‚ NEDD4-1 mainly promotes the proliferation‚ invasion and migration of hepatocellular carcinoma through multiple pathways such as PTEN/ PI3K/ Akt‚ TGF-β‚ Hippo and LDLRAD4. In pancreatic cancer‚ NEDD4-1 acted as an oncogene in the PI3K/ Akt signaling pathway‚ but acted as a tumor suppressor gene in the Myc-Sirt2 signaling circuit. In gastric and colorectal cancer‚ the NEDD4-1-related signaling pathways are different from other digestive system tumors. NEDD4-1 promotes gastric cancer progression and metastasis (via the EGFR signaling pathway) and inhibits colorectal cancer tumor growth (via the Wnt signaling pathway) independently of the PTEN/ PI3K/ Akt pathway. NEDD4-1 has become a hot research direction for therapeutic purposes. In this paper‚ we summarize the functions‚ signaling pathways and potential inhibitors of NEDD4-1 in different digestive system tumors‚ and discuss the relationship between NEDD4-1 and different signaling pathways‚ aiming to provide important reference data for cancer therapy.