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Last update 08 May 2025

TMBIM6

Last update 08 May 2025

Basic Info

Synonyms

Bax inhibitor 1, BAXI1, BI-1

+ [6]

Introduction

Endoplasmic reticulum (ER)-resident protein that confers cellular protection as an anti-apoptotic protein by limiting multiple stress-inducing pathways surrounding the endoplasmic reticulum and mitochondria (PubMed:21075086, PubMed:21068390). Inhibits the activities of the key sensor for the endoplasmic reticulum unfolded protein response IRE1alpha/ERN1 both directly and by blocking BAX/BAK binding (PubMed:19328063). 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

306

Literatures (Medical) associated with TMBIM6

18 Apr 2025·Oncogene

Global profiling of alternative splicing in non-small cell lung cancer reveals novel histological and population differences

Article

Author: Khiabanian, Hossein ; Harris, Curtis C ; Pine, Sharon R ; Zeeshan, Saman ; Zingone, Adriana ; Arauz, Rony F ; Ryan, Bríd M ; Dalal, Bhavik

Lung cancer is one of the most frequently diagnosed cancers in the US. African-American (AA) men are more likely to develop lung cancer with higher incidence and mortality rates than European-American (EA) men. Herein, we report high-confidence alternative splicing (AS) events from high-throughput, high-depth total RNA sequencing of lung tumors and non-tumor adjacent tissues (NATs) in two independent cohorts of patients with adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). We identified novel AS biomarkers with notable differential percent spliced in (PSI) values between lung tumors and NATs enriched in the AA and EA populations, which were associated with oncogenic signaling pathways. We also uncovered tumor subtype- and population-specific AS events associated with cell surface proteins and cancer driver genes. We highlighted significant AS events in SYNE2 specific to LUAD in both populations, as well as those in CD44 from EAs and TMBIM6 from AAs specific to LUAD. Here, we also present the validation of cancer signatures based on direct high-throughput reverse transcription-PCR. Our large survey of lung tumors presents a rich data resource that may help to understand molecular subtypes of lung tumor between AAs and EAs and reveal new therapeutic vulnerabilities that potentially advance health equity.

10 Mar 2025·Oncogene

TMBIM6/BI-1 is an intracellular environmental regulator that induces paraptosis in cancer via ROS and Calcium-activated ERAD II pathways

Article

Author: Sennhenn, Peter ; Robinson, Keith S ; Taddei, David ; Qian, Yue ; Luo, Wei ; Yuan, Daniel S ; Liu, Hai

Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, also known as Bax Inhibitor-1 (BI-1), has been heavily researched for its cytoprotective functions. TMBIM6 functional diversity includes modulating cell survival, stress, metabolism, cytoskeletal dynamics, organelle function, regulating cytosolic acidification, calcium, and reactive oxygen species (ROS). Clinical research shows TMBIM6 plays a key role in many of the world's top diseases/injuries (i.e., Alzheimer's, Parkinson's, diabetes, obesity, brain injury, liver disease, heart disease, aging, etc.), including cancer, where TMBIM6 expression impacts patient survival, chemoresistance, cancer progression, and metastasis. We show TMBIM6 is activated by, and undergoes, different conformational changes that dictate its function following a significant change in the cell's IntraCellular Environment (ICE). TMBIM6 agonism, following ICE change, can help the cell overcome multiple stresses including toxin exposure, viral infection, wound healing, and excitotoxicity. However, in cancer cells TMBIM6 agonism results in rapid paraptotic induction irrespective of the cancer type, sub-type, genotype or phenotype. Furthermore, the level of TMBIM6 expression in cancer did not dictate the level of paraptotic induction; however, it did dictate the rate at which paraptosis occurred. TMBIM6 agonism did not induce paraptosis in cancer via canonical routes involving p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9. Instead, TMBIM6 agonism in cancer upregulates cytosolic Ca2+ and ROS, activates lysosome biogenesis, and induces paraptosis via ERAD II mechanisms. In xenograft models, we show TMBIM6 agonism induces rapid cancer cell death with no toxicity, even at high doses of TMBIM6 agonist (>450 mg/kg). In summary, this study shows TMBIM6's functional diversity is only activated by severe ICE change in diseased/injured cells, highlighting its transformative potential as a therapeutic target across various diseases and injuries, including cancer.

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.

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TMBIM6

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