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bioRxiv · 10.1101/2025.11.03.686179

Lrrc55 modulates beta-cell resilience and calcium transporter expression under metabolic and physiologic stress

Pretorius, M.·Kahlon, R.·Xie, Q.·Huang, C.
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Abstract

During pregnancy, pancreatic {beta}-cell mass and function are increased in adaptation to insulin resistance; this requires the action of prolactin receptor signaling. Recently, we discovered the Lrrc55, an auxiliary subunit of the voltage- and calcium-activated potassium channel (BK channel), is a prosurvival factor in {beta}-cell, and its expression and highly and specifically up regulated in the pancreatic islets during pregnancy. We found that overexpression of Lrrc55 protects {beta}-cells from glucolipotoxicity (GLT)-induced apoptosis. The protective effect of Lrrc55 is associated with dampening of the ER stress response and preservation of the releasable pool of calcium in the ER. Thus, we hypothesized that Lrrc55 protects {beta}-cells from GLT-induced ER stress and apoptosis by regulating ER calcium handling. Here, we report that Lrrc55 restored the GLT-mediated decrease in expression levels the insulin regulators, Pdx-1 and MafA, as well as the ER calcium regulator SERCA. Lrrc55 also attenuated the GLT-induced increase in expression of the ER calcium channel RyR2. Lrrc55 also attenuated GLT-mediated increase in protein expression of pro-apoptotic molecules CHOP and IRE1, and increased activation of the anti-apoptotic molecule Akt. However, Lrrc55 does not alter the activity levels of SERCA or IP3R under physiologic conditions. Transgenic mice with global deletion of Lrrc55 (Lrrc55-/-) are more susceptible to streptozotocin-induced diabetes. Surprisingly, Lrrc55-/- mice are more glucose tolerant and secreted more insulin during pregnancy. Together, these results suggest a role for Lrrc55 in maintaining expression of the ER calcium regulators in the presence of GLT but it may negatively regulate insulin secretion.

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Pretorius, M., Kahlon, R., Xie, Q., Huang, C.. 2025-11-05. Lrrc55 modulates beta-cell resilience and calcium transporter expression under metabolic and physiologic stress. https://doi.org/10.1101/2025.11.03.686179

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