Leucine rich repeat containing protein 8B (LRRC8B) - A novel modulator of endoplasmic reticulum (ER) stress response

The endoplasmic reticulum (ER), a major calcium ion (Ca²⁺) reservoir, plays a pivotal role in lipid synthesis, protein synthesis, and secretion. Disruption of ER function leads to the accumulation of misfolded proteins, resulting in ER stress. To restore cellular homeostasis, the unfolded protein response (UPR) is activated. However, prolonged or irreversible ER stress can trigger apoptosis and cell death. Cellular dysfunction and apoptosis arising from disrupted ER Ca²⁺ homeostasis are often implicated in neurodegenerative and metabolic disorders. We investigated the role of LRRC8B, an ER-resident protein previously linked to ER Ca²⁺ homeostasis, in the ER stress response. LRRC8B expression was upregulated in response to chemically induced ER stress. Overexpression of LRRC8B enhanced the viability of HEK293T cells exposed to the ER stressor tunicamycin, whereas LRRC8B knockdown increased their susceptibility to apoptosis. Furthermore, LRRC8B overexpression reduced protein aggregation during ER stress by upregulating cytoprotective genes associated with the adaptive UPR, including BiP, calnexin, and PDI. Conversely, LRRC8B knockdown decreased BiP expression and elevated the levels of ER stress-induced apoptotic proteins such as CHOP, Bax, and cleaved caspase-3. Co-treatment with the chemical chaperone, 4-PBA, partially rescued the LRRC8B knockdown cells undergoing apoptosis. In Neuro 2a (N2a) cells, LRRC8B overexpression diminished the aggregation of mutant huntingtin protein (HTT-83Q), associated with Huntington's disease, whereas its knockdown exacerbated HTT-83Q aggregation. Taken together, these findings suggest that LRRC8B is a key modulator of the ER stress response and plays a cytoprotective role.