TMBIM6 connects endoplasmic reticulum stress with changes in calcium homeostasis

• Applicant: Professor Dr. Axel Methner
• Subject Area: Biochemistry ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566971919

Endoplasmic reticulum (ER) stress and calcium (Ca²⁺) homeostasis are crucial regulators of cellular function, with significant implications for metabolic disorders, neurodegeneration, and aging-related diseases. Transmembrane BAX Inhibitor Motif Containing 6 (TMBIM6) has been identified as a key modulator of ER stress responses through its interactions with inositol-requiring enzyme 1 alpha (IRE1α) and sarco/endoplasmic reticulum Ca²⁺-ATPase 2b (SERCA2b). This study aims to elucidate the molecular mechanisms by which TMBIM6 influences IRE1α oligomerization, SERCA2b activity, and their coordinated roles in calcium homeostasis and the unfolded protein response (UPR). We hypothesize that TMBIM6 acts as a Ca²⁺-sensitive regulator, influencing both IRE1α-mediated ER stress signaling and SERCA2b-dependent Ca²⁺ dynamics. To test this, we will examine the structural and biochemical interactions between TMBIM6, IRE1α, and SERCA2b under ER stress conditions using high-resolution imaging, immunoprecipitation, molecular docking, and proteomics. Additionally, we will investigate whether NAADP-induced Ca²⁺ release, a key modulator of intracellular Ca²⁺ dynamics, plays a role in regulating IRE1α and SERCA2b function. The project will further assess how TMBIM6 influences regulated IRE1-dependent decay (RIDD) activity, UPR signaling, and cell fate under physiological and pathological conditions. By integrating cellular and molecular analyses, this study aims to uncover the intricate crosstalk between Ca²⁺ homeostasis, IRE1α signaling, and SERCA2b function, providing novel insights into ER stress adaptation. Our findings will contribute to a deeper understanding of how ER stress regulation is linked to metabolic and neurodegenerative diseases, potentially identifying TMBIM6 as a therapeutic target for conditions associated with ER dysfunction and impaired calcium signaling.

• DFG Programme: Research Grants
• International Connection: South Korea
• Partner Organisation: National Research Foundation of Korea, NRF
• Cooperation Partner: Professorin Han-Jung Chae, Ph.D.