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Last update 23 Jan 2025

TMBIM6

Last update 23 Jan 2025

Basic Info

Synonyms

Bax inhibitor 1, BAXI1, BI-1

+ [6]

Introduction

Suppressor of apoptosis (PubMed:21075086). Modulates unfolded protein response signaling (PubMed:21075086). Modulates ER calcium homeostasis by acting as a calcium-leak channel (PubMed:22128171). Negatively regulates autophagy and autophagosome formation, especially during periods of nutrient deprivation, and reduces cell survival during starvation (By similarity).

Drugs associated with TMBIM6

Ginsenoside Rb1

Target

DUSP1 x MFN2 x TMBIM6 x VDAC1

Mechanism

DUSP1 modulators [+3]

Active Org.

Chinese Medical Sciences China Academy [+7]

Originator Org.

Chinese Medical Sciences China Academy

Active Indication

Heart Failure [+7]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TMBIM6

100 Translational Medicine associated with TMBIM6

0 Patents (Medical) associated with TMBIM6

327

Literatures (Medical) associated with TMBIM6

01 Mar 2025·Respiratory Investigation

LPS-induced TMBIM6 splicing drives endothelial necroptosis and aggravates ALI

Article

Author: Liu, Yaling ; Wang, Xiaodong ; Chen, Hao ; Gao, Yang ; Zhu, Hao ; Xie, Hong ; Wang, Tingyin

BACKGROUNDThe mechanism underlying necroptosis in pulmonary vessel endothelial cells (PVECs) resulting from long non-coding RNA (lncRNA)-induced alternative splicing (AS) of target genes in acute lung injury (ALI) remains unclear.METHODSLipopolysaccharide (LPS)-induced expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and lncRNAs was analyzed via RT-PCR in PVECs. Full-transcriptome sequencing was used to detect AS-related mRNAs. The interaction between lncRNA MALAT1 and target gene transmembrane BAX inhibitor motif-containing 6 (TMBIM6) was verified using a dual-luciferase reporter system. Necroptosis was measured as protein levels of phosphorylated receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like (MLKL) proteins, as well as flow cytometer measurement. Antisense of MALAT1, TMBIM6, TMBIM6-225 and RIPK1 inhibitor were transfected into a rat model of LPS-induced ALI. Hematoxylin and eosin (H&E) and immunohistochemical staining were performed to evaluate lung injury.RESULTSLPS upregulated the expression of TNF-α, IL-1β, IL-6, p-RIPK1, p-RIPK3, p-MLKL, MALAT1, and TMBIM6-225 (an AS isoform of MALAT1-targeted gene TMBIM6) in PVECs. However, it downregulated the expression of TMBIM6. An antisense of MALAT1 inhibited TMBIM6-225 and downregulated p-MLKL. The pro-necroptotic effect of MALAT1 was verified in an LPS-induced MALAT1/shMALAT1-transfected ALI rat model in vivo. The necroptotic effect was reversed by treatment with necrostatin-1.CONCLUSIONSLPS-induced MALAT1 causes AS of TMBIM6, and the AS variant TMBIM6-225 aggravates ALI by promoting PVEC necroptosis via the p-RIPK1, p-RIPK3, and p-MLKL complex.

01 Jan 2025·Molecular Neurobiology

BI1 Activates Autophagy and Mediates TDP43 to Regulate ALS Pathogenesis

Article

Author: Fu, Xueqi ; Zeng, Linlin ; Wang, Yuxiang ; Ma, Xueting ; Zhang, Fuqiang ; Xiao, Zixuan ; Yin, Hanlan ; Ren, Zhichao ; Zhang, Jingtian ; Wang, Yu

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease in adults. Currently, there are no known drugs or clinical approaches that have demonstrated efficacy in treating ALS. Mitochondrial function and autophagy have been identified as crucial mechanisms in the development of ALS. While Bax inhibitor 1 (BI1) has been implicated in neurodegenerative diseases, its exact mechanism remains unknown. This study investigates the therapeutic impact of BI1 overexpression on ALS both in vivo and in vitro, revealing its ability to mitigate SOD1^G93A-induced apoptosis, nuclear damage, mitochondrial dysfunction, and axonal degeneration of motor neurons. At the same time, BI1 prolongs onset time and lifespan of ALS mice, improves motor function, and alleviates neuronal damage, muscle damage, neuromuscular junction damage among other aspects. The findings indicate that BI1 can inhibit pathological TDP43 morphology and initially stimulate autophagy through interaction with TDP43. This study establishes a solid theoretical foundation for understanding the regulation of autophagy by BI1 and TDP43 while shedding light on the pathogenesis of ALS through their interaction - offering new concepts and targets for clinical implementation and drug development.

01 Jan 2025·Immunity

Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation

Article

Author: Montenegro Navarro, Jasmine ; Haanen, John B A G ; Voogd, Rhianne ; Fumagalli, Amos ; Champagne, Julien ; van de Ven, Marieke ; Berenst, Nadine ; Nielsen, Morten M ; Yang, Weiwen ; Giebel, Lisanne ; van Tellingen, Olaf ; Olweus, Johanna ; Feng, Xiaodong ; Lovecchio, Domenica ; Laos, Maarja ; Valcanover, Lorenzo ; Nagel, Remco ; Pataskar, Abhijeet ; Proost, Natalie ; Agami, Reuven ; Bleijerveld, Onno B ; Li, Yingqian ; Malka, Yuval ; Kochavi, Adva

Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A^∗24:02 allele. We identified a T cell receptor (TCR^TMBIM6W>F.1) possessing high affinity and specificity toward TMBIM6^W>F/HLA-A^∗24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCR^TMBIM6W>F.1 T cells are activated by tryptophan-depleted cancer cells but not by non-cancer cells. Finally, we provide in vivo proof of concept for clinical application, whereby TCR^MART1 T cells promote cancer cell killing by TCR^TMBIM6W>F.1 T cells through the generation of W>F neoepitopes. Thus, neoepitopes arising from W>F substitution present shared and highly expressed immunogenic targets with the potential to overcome current limitations in adoptive T cell therapy.

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TMBIM6

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