Structural basis for a novel interaction between <scp>TXNIP</scp> and Vav2

Li, Shasha; Wu, Xue; Zong, Minru; Tempel, W.; Loppnau, P.; Li, Yanli

doi:10.1002/1873-3468.12110

Cited by 6 publications

(4 citation statements)

References 64 publications

(78 reference statements)

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“…In humans, the NEDD family has nine members: NEDD4, NEDD4L, WWP1, WWP2, ITCH, SMURF1, SMURF2, HECW1, and HECW2 [ 120 ]. TXNIP undergoes proteasomal degradation by polyubiquitination through the physical interaction with the HECT ubiquitin ligase ITCH [ 122 , 123 , 124 , 125 ]. In contrast, TXNIP stabilizes p53 expression by interacting with human ecdysoneless (hEcd), which is known for its role in stabilizing p53 protein expression [ 126 ].…”

Section: Txnip/tbp-2 In Molecular Functionsmentioning

confidence: 99%

TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Yoshihara

2020

Antioxidants

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Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

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Section: Txnip/tbp-2 In Molecular Functionsmentioning

confidence: 99%

TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Yoshihara

2020

Antioxidants

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“…We have shown that by sensing intracellular ROS during hHcys, thioredoxin-interacting protein (TXNIP) associates with NLRP3 to trigger the cascade of downstream events leading to inflammasome activation 36 . Recently, evidence links Vav2 as a binding partner of TXNIP 37 . Therefore, we sought to identify whether the detrimental actions of Vav2 is involved in NLRP3 inflammasome assembling, activation and subsequent podocyte dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Contribution of guanine nucleotide exchange factor Vav2 to NLRP3 inflammasome activation in mouse podocytes during hyperhomocysteinemia

Conley

Abais‐Battad

Yuan

et al. 2017

Free Radical Biology and Medicine

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NADPH oxidase (NOX)-derived reactive oxygen species (ROS) have been demonstrated to mediate the activation of NOD-like receptor protein 3 (NLRP3) inflammasomes in podocytes in response to elevated levels of homocysteine (Hcys). However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The present study tested whether the guanine nucleotide exchange factor Vav2 mediates Rac1-mediated NOX activation in response to elevated Hcys leading to NLRP3 inflammasome activation in podocytes and consequent glomerular injury. In a mouse model of hyperhomocysteinemia (hHcys), we found that mice with hHcys (on the FF diet) or oncoVav2 (a constitutively active form of Vav2) transfection in the kidney exhibited increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1 and elevated IL-1β levels in glomeruli, indicating the formation and activation of the NLRP3 inflammasome. This glomerular NLRP3 inflammasome activation was accompanied by podocyte dysfunction and glomerular injury, even sclerosis. Local transfection of Vav2 shRNA plasmids significantly attenuated hHcys-induced NLRP3 inflammasome activation, podocyte injury, and glomerular sclerosis. In cultured podocytes, Hcys treatment and oncoVav2 transfection were also found to increase NLRP3 inflammasome formation and activation, which were all inhibited by Vav2 shRNA. Furthermore, Vav2 shRNA prevented Hcys-induced podocyte damage as shown by restoring Hcys-impaired VEGF secretion and podocin production. This inhibitory action of Vav2 shRNA on Hcys-induced podocyte injury was associated with reduction of Rac1 activity and ROS production. These results suggest that elevated Hcys levels activate Vav2 and thereby increase NOX activity leading to ROS production, which triggers NLRP3 inflammasome activation, podocyte dysfunction and glomerular injury.

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“…TXNIP is important for regulating mitochondrial function, inducing apoptosis, and inhibiting growth and metastasis; in addition, it also plays roles in the development of natural killer cells, promoting cell-cycle arrest and regulating glucose metabolism and inflammatory signaling (8)(9)(10). TXNIP belongs to the αarrestin protein family (11), the members of which have two domains, namely, SH3 and PPxY (12); through these domains, TXNIP can interact with other proteins to perform different biological roles. (TABLE 1) TXNIP and Breast Cancer Breast cancer arises from breast epithelial tissue.…”

Section: Introductionmentioning

confidence: 99%

Research Progress of TXNIP as a Tumor Suppressor Gene Participating in the Metabolic Reprogramming and Oxidative Stress of Cancer Cells in Various Cancers

et al. 2020

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Thioredoxin-interacting protein (TXNIP) is a thioredoxin-binding protein that can mediate oxidative stress, inhibit cell proliferation, and induce apoptosis by inhibiting the function of the thioredoxin system. TXNIP is important because of its wide range of functions in cardiovascular diseases, neurodegenerative diseases, cancer, diabetes, and other diseases. Increasing evidence has shown that TXNIP expression is low in tumors and that it may act as a tumor suppressor in various cancer types such as hepatocarcinoma, breast cancer, and lung cancer. TXNIP is known to inhibit the proliferation of breast cancer cells by affecting metabolic reprogramming and can affect the invasion and migration of breast cancer cells through the TXNIP-HIF1α-TWIST signaling axis. TXNIP can also prevent the occurrence of bladder cancer by inhibiting the activation of ERK, which inhibits apoptosis in bladder cancer cells. In this review, we find that TXNIP can be regulated by binding to transcription factors or other binding proteins and can also be downregulated by epigenetic changes or miRNA. In addition, we also summarize emerging insights on TXNIP expression and its functional role in different kinds of cancers, as well as clarify its participation in metabolic reprogramming and oxidative stress in cancer cells, wherein it acts as a putative tumor suppressor gene to inhibit the proliferation, invasion, and migration of different tumor cells as well as promote apoptosis in these cells. TXNIP may therefore be of basic and clinical significance for finding novel molecular targets that can facilitate the diagnosis and treatment of malignant tumors.

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Structural basis for a novel interaction between TXNIP and Vav2

Cited by 6 publications

References 64 publications

TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Contribution of guanine nucleotide exchange factor Vav2 to NLRP3 inflammasome activation in mouse podocytes during hyperhomocysteinemia

Research Progress of TXNIP as a Tumor Suppressor Gene Participating in the Metabolic Reprogramming and Oxidative Stress of Cancer Cells in Various Cancers

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