Coupling lysosomal polarity and purinergic signaling regulates B cell activation

Alamo Rollandi, M.; Bozo, J. P.; Riobo Cavada, I.; Lopez-Lopez, T.; Kux, J. M.; Jaeckstein, M.; Rissiek, B.; Heeren, J.; Sauma, D.; Saez, P. J.; Yuseff, M. I.

doi:10.64898/2026.09.15.751411

bioRxiv · 10.64898/2026.09.15.751411

Coupling lysosomal polarity and purinergic signaling regulates B cell activation

Alamo Rollandi, M.·Bozo, J. P.·Riobo Cavada, I.·Lopez-Lopez, T.·Kux, J. M.·Jaeckstein, M.·Rissiek, B.·Heeren, J.·Sauma, D.·Saez, P. J.·Yuseff, M. I.

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Abstract

B cell activation is initiated by engagement of the B cell receptor (BCR) with immobilized antigens, which triggers changes in cell polarity promoting the establishment of an immune synapse that is further shaped by signals from the microenvironment. However, how cell polarity coordinates the sensing of extracellular cues to regulate B cell activation remains unclear. Here, we investigated the impact of adenosine triphosphate (ATP), a conventional danger signal related to inflammation, on B cell function. We found that ATP released by B cells, as well as exogenously added ATP, acts as a promoter of the extraction and presentation of immobilized antigens. Endogenous ATP was produced by mitochondria recruited at the immune synapse and locally released via Pannexin 1 channels to sustain purinergic signaling at the immune synapse. We identified P2RX4 trafficking to the plasma membrane through the Rab6a+ trans-Golgi network and VAMP7+/LAMP1+ lysosomes as a key step in this response. In addition, the local activation of P2RX4 at the immune synapse triggered a migratory switch from motile to sessile, suggesting that this receptor acts as a negative regulator of B cell migration. These findings reveal ATP as a local enhancer of B cell function, and an unexpected role of P2RX4 as a molecular switch for B cell activation.

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Alamo Rollandi, M., Bozo, J. P., Riobo Cavada, I., Lopez-Lopez, T., Kux, J. M., Jaeckstein, M., Rissiek, B., Heeren, J., Sauma, D., Saez, P. J., Yuseff, M. I.. 2026-09-21. Coupling lysosomal polarity and purinergic signaling regulates B cell activation. https://doi.org/10.64898/2026.09.15.751411

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