The revolutionary Proteolysis Targeting Chimera (PROTACs) have the exciting potential to reshape the pharmaceutical industry landscape by leveraging the ubiquitin-proteasome system for targeted protein degradation. Breast cancer, the most prevalent cancer in women, could be treated using PROTAC therapy. Although substantial work has been conducted, there is not yet a comprehensive overview or progress update on PROTAC therapy for breast cancer. Hence, in this article, we\'ve compiled recent research progress focusing on different breast cancer target proteins, such as estrogen receptor (ER), BET, CDK, HER2, PARP, EZH2, etc. This resource aims to serve as a guide for future PROTAC-based breast cancer treatment design.

UNASSIGNED: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.
UNASSIGNED: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.
UNASSIGNED: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.
UNASSIGNED: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

OBJECTIVE: Although a virus can regulate many cellular responses to facilitate its replication by interacting with host proteins, the host can also restrict virus infection through these interactions. In the present study, we showed that the host eukaryotic translation elongation factor 1 alpha (eEF1A), an essential protein in the translation machinery, interacted with two proteins of a fish rhabdovirus, Siniperca chuatsi rhabdovirus (SCRV), and inhibited virus infection via two different mechanisms: (i) inhibiting the formation of crucial viral protein complexes required for virus transcription and replication and (ii) promoting the ubiquitin-proteasome degradation of viral protein. We also revealed the functional regions of eEF1A that are involved in the two processes. Such a host protein inhibiting a rhabdovirus infection in two ways is rarely reported. These findings provided new information for the interactions between host and fish rhabdovirus.

Plant viruses are tiny pathogenic obligate parasites that cause significant damage to global crop production. They exploit and manipulate the cellular components of host plants to ensure their own survival. In response, plants activate multiple defense signaling pathways, such as gene silencing and plant hormone signaling, to hinder virus propagation. Growing evidence suggests that the regulation of protein homeostasis plays a vital role in the ongoing battle between plants and viruses. The ubiquitin-proteasome-degradation system (UPS) and autophagy, as two major protein-degradation pathways, are widely utilized by plants and viruses in their arms race. One the one hand, these pathways act as essential components of plant\'s antiviral defense system by facilitating the degradation of viral proteins; on the other hand, viruses exploit the UPS and autophagy to create a favorable intracellular environment for viral infection. This review aims to provide a comprehensive summary of the events involved in protein homeostasis regulation during viral infection in plants. Gaining knowledge in this area will enhance our understanding of the complex interplay between plants and viruses.

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PD-L1 interacts with its receptor PD-1 on T cells to negatively regulate T cell function, leading to cancer cell immune escape from the immune surveillance. Therefore, targeting PD-L1 is considered to be an attractive approach for cancer immunotherapy. In this study, we demonstrated for the first time that ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduced the expression of PD-L1 in cancer cells both in vitro and in vivo. Promotion of PD-L1 ubiquitin-proteasome degradation by DHA resulted in a decrease of PD-L1 expression, leading to reduction of PD-L1 and PD-1 interaction, and reversing PD-L1-mediated immune suppression, which in turn contributed to the inhibitory effect on tumor growth. Furtherly, DHA significantly reduced fatty acid synthase (FASN) expression in cancer cells, which inhibited the palmitoyltransferases DHHC5, promoting the CSN5-dependent PD-L1 degradation. Our present finding uncovered a novel mechanism involved in the anti-cancer activity of DHA, and implicated that DHA holds promising potential to be developed as a novel immune-enhancer for cancer treatment and prevention.

Discography often destroys the hypoxic environment in the intervertebral disc and accelerates intervertebral disc degeneration (IVDD). Therefore, it often fails to meet the requirements for application in clinical practice. This technology mainly increases the reactive oxygen species (ROS) in the IVD. As so, it is particularly critical to develop strategies to avoid this degeneration mechanism. Prussian blue nanoparticles (PBNPs) are found to enhance development under magnetic resonance T1 and have antioxidant enzyme activity. The key results of the present study confirm that PBNPs alleviate intracellular oxidative stress and increase the intracellular activities of antioxidant enzymes, such as superoxide dismutase 1 (SOD1). PBNPs can rescue nucleus pulposus cell degeneration by increasing oxidoreductase system-related mRNA and proteins, especially by stabilizing SOD1 from ubiquitination-proteasome degradation, thus improving the mitochondrial structure to increase antioxidation ability, and finally rescuing ROS-induced IVDD in a rat model. Therefore, it is considered that PBNPs can be a potential antioxidation-protective discography contrast agent.

Serum and glucocorticoid-inducible kinase 3 (SGK3) is involved in maintaining podocyte function by regulating the protein levels of podocin and CD2-associated protein. Nephrin is also one of the slit diaphragm proteins of podocytes, but whether SGK3 participates in podocyte injury by regulating the levels of nephrin remains unclear. In this study, we focused on whether SGK3 affects nephrin levels and the mechanisms involved in the same. In the kidneys of adriamycin (ADR)-induced podocyte injury mouse model, the protein levels of SGK3 and nephrin were significantly decreased. Furthermore, the expression of SGK3 was negatively correlated with the output of proteinuria, and positively correlated with the levels of nephrin. In ADR-treated conditionally immortalized mouse podocyte cells (MPCs), the protein levels of nephrin and SGK3 were inhibited, while the constitutive expression of SGK3 reversed the ADR-induced decline in nephrin protein levels. Furthermore, ADR treatment or SGK3 inactivation enhanced the ubiquitin-proteasome degradation of nephrin in MPCs, and dramatically activated downstream effector proteins of SGK3, neural precursor cells expressing developmentally downregulated protein 4 subtype 2 (Nedd4-2) and glycogen synthase kinase-3 β (GSK3β). Similarly, Nedd4-2 or GSK3β overexpression resulted in increased activity of Nedd4-2 or GSK3β, and significantly downregulated nephrin levels. Interestingly, ubiquitin-mediated protein degradation of nephrin was regulated by Nedd4-2, rather than by GSK3β. In summary, SGK3 inactivation downregulated the levels of nephrin by increasing Nedd4-2 and GSK3β activity in ADR-induced podocyte injury model; in particular, the SGK3/Nedd4-2 signaling pathway was found to be involved in ubiquitin-mediated proteasome degradation of nephrin.

SAMHD1 possesses multiple functions, but whether cellular factors regulate SAMHD1 expression or its function remains not well characterized. Here, by investigating why cultured RD and HEK293T cells show different sensitivity to enterovirus 71 (EV71) infection, we demonstrate that SAMHD1 is a restriction factor for EV71. Importantly, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator of SAMHD1, which specifically interacts and degrades SAMHD1 through the proteasomal pathway. However, TRIM21 has no effect on EV71 replication itself. Moreover, we prove that interferon production stimulated by EV71 infection induces increased TRIM21 and SAMHD1 expression, whereas increasing TRIM21 overrides SAMHD1 inhibition of EV71 in cells and in a neonatal mouse model. TRIM21-mediated degradation of SAMHD1 also affects SAMHD1-dependent restriction of HIV-1 and the regulation of interferon production. We further identify the functional domains in TRIM21 required for SAMHD1 binding and the ubiquitination site K622 in SAMHD1 and show that phosphorylation of SAMHD1 at T592 also blocks EV71 restriction. Our findings illuminate how EV71 overcomes SAMHD1 inhibition via the upregulation of TRIM21.

Metadherin (MTDH) is an oncoprotein and is expressed at high levels in a wide variety of human carcinomas, which represents an important genetic determinant and regulates multiple events in tumorigenesis. MTDH promotes breast cancer cell proliferation and tumorigenesis through the activation of numerous signaling pathways. Currently, the mecha- nism regulating MTDH expression is poorly understood. Here we identified that FBXW7, a component of E3 ubiquitin ligase, targets MTDH for ubiquitin-mediated degradation. Forced overexpression of FBXW7 could decrease the level of MTDH protein, and inhibition of endogenous FBXW7 expression remarkably increases the MTDH protein abundance. More importantly, overexpression of FBXW7 could lead to proliferation arrest and apoptosis in breast cancer cells through targeting MTDH degradation. These data suggest that FBXW7, a tumor suppressor, inhibits breast cancer cell prolifera- tion and promotes apoptosis at least partially through targeting MTDH for proteolysis. This new regulatory mechanism of MTDH by FBXW7 represents a new pathway for malignant phenotype turnover in human breast cancer.