Robinson Keith S, Sennhenn Peter, Yuan Daniel S, Liu Hai, Taddei David, Qian Yue, Luo Wei
MicroQuin, Cambridge, MA, USA.
Viva Biotech, Shanghai, China.
Oncogene. 2025 Mar;44(8):494-512. doi: 10.1038/s41388-024-03222-x. Epub 2024 Nov 29.
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.
跨膜B细胞淋巴瘤2相关X蛋白抑制基序包含蛋白（TMBIM）6，也称为Bax抑制剂-1（BI-1），因其细胞保护功能而受到广泛研究。TMBIM6的功能多样性包括调节细胞存活、应激、代谢、细胞骨架动力学、细胞器功能、调节胞质酸化、钙和活性氧（ROS）。临床研究表明，TMBIM6在世界上许多主要疾病/损伤（如阿尔茨海默病、帕金森病、糖尿病、肥胖症、脑损伤、肝病、心脏病、衰老等）中起关键作用，包括癌症，其中TMBIM6的表达会影响患者的生存、化疗耐药性、癌症进展和转移。我们发现，TMBIM6在细胞内环境（ICE）发生重大变化后，会被激活并经历不同的构象变化，这些变化决定了它的功能。ICE变化后，TMBIM6激动作用可帮助细胞克服多种应激，包括毒素暴露、病毒感染、伤口愈合和兴奋性毒性。然而，在癌细胞中，无论癌症类型、亚型、基因型或表型如何，TMBIM6激动作用都会导致快速的副凋亡诱导。此外，癌症中TMBIM6的表达水平并不决定副凋亡诱导的程度；然而，它确实决定了副凋亡发生的速率。TMBIM6激动作用不会通过涉及p38丝裂原活化蛋白激酶、c-Jun氨基末端激酶、细胞外信号调节激酶、未折叠蛋白反应、自噬、蛋白酶体或半胱天冬酶-9的经典途径在癌症中诱导副凋亡。相反，癌症中的TMBIM6激动作用会上调胞质Ca2+和ROS，激活溶酶体生物发生，并通过内质网相关降解II机制诱导副凋亡。在异种移植模型中，我们发现TMBIM6激动作用即使在高剂量的TMBIM6激动剂（>450mg/kg）下也能诱导癌细胞快速死亡且无毒性。总之，这项研究表明，TMBIM6的功能多样性仅在患病/受伤细胞的严重ICE变化时被激活，突出了其作为包括癌症在内的各种疾病和损伤的治疗靶点的变革潜力。
