The Endoplasmic Reticulum (ER) is a highly dynamic structure crucial for various cellular processes, including calcium storage, lipid synthesis, and protein translation, folding, and maturation. ER stress occurs when the folding capacity of the ER is overwhelmed, leading to the accumulation of misfolded protein aggregates within its lumen. This phenomenon initiates the Unfolded Protein Response (UPR) pathway as an adaptive mechanism, which involves suppressing translation, enhancing ER protein folding capacity via increased chaperone expression, and activating ER Associated Degradation (ERAD) to eliminate misfolded proteins. However, prolonged ER stress shifts from adaptive to pro-apoptotic signaling, ultimately resulting in cell death. ER stress-induced cell death contributes significantly to various pathological conditions, such as diabetes, neurodegenerative diseases, cancer, and others.

Previous studies in our lab have identified LRRC8B, a non-essential component of the Volume Regulated Anion Channel (VRAC), localized within the ER and associated with calcium leakage from the ER into the cytosol. This suggests that LRRC8B may play a pivotal role in ER stress by modulating ER calcium homeostasis. Therefore, we investigated the involvement of LRRC8B in ER stress.

Our findings indicate that LRRC8B expression increases when HEK293T cells are exposed to tunicamycin, an ER stress inducer. Moreover, knockdown of LRRC8B renders cells more susceptible to tunicamycin-induced cell death. Conversely, overexpression of LRRC8B mitigates protein aggregation during ER stress by upregulating cytoprotective genes such as ATF4 and ER-resident chaperones. Furthermore, LRRC8B is abundantly expressed in the brain. We discovered that overexpression of LRRC8B in N2a cells can attenuate 83Q HTT (Huntingtin) protein aggregates associated with Huntington’s disease, while knockdown of LRRC8B exacerbates the aggregation phenotype. Based on these observations, we propose that LRRC8B-mediated modulation of ER calcium homeostasis triggers the adaptive pathway of ER stress, mitigates misfolded protein aggregation, and reduces cell susceptibility to apoptosis. These findings shed light on the potential therapeutic significance of LRRC8B in managing ER stress-related diseases.