Phosphatases of regenerating liver balance F-actin rearrangements during T cell activation through WD repeat containing protein 1

Aguilar-Sopena, O.; Carrasco-Padilla, C.; Gomez-Moron, A.; Castro-Sanchez, P.; Estaras-Hermosel, M.; Valvo, S.; Alegre-Gomez, S.; Redondo-Munoz, J.; Torres, R.; Rodriguez-Perales, S.; Ismail, S.; Sanchez-Madrid, F.; Martin-Cofreces, N. B.; Dustin, M. L.; Navarro, P. R.

doi:10.1101/2023.12.28.573244

bioRxiv · 10.1101/2023.12.28.573244

Phosphatases of regenerating liver balance F-actin rearrangements during T cell activation through WD repeat containing protein 1

Aguilar-Sopena, O.·Carrasco-Padilla, C.·Gomez-Moron, A.·Castro-Sanchez, P.·Estaras-Hermosel, M.·Valvo, S.·Alegre-Gomez, S.·Redondo-Munoz, J.·Torres, R.·Rodriguez-Perales, S.·Ismail, S.·Sanchez-Madrid, F.·Martin-Cofreces, N. B.·Dustin, M. L.·Navarro, P. R.

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Abstract

Phosphatases of regenerating liver (PRLs) have been proposed to regulate actin dynamics in lymphoid cells. However, the mechanism mediating this role remained unknown. Here we showed the interaction of the PRLs with the actin regulator WD repeat containing protein 1 (WDR1). The interaction of the PRLs with WDR1 was dependent on F-actin integrity and the proper recruitment of the PRLs to cell membranes through the CAAX motif. Endogenous PRLs and WDR1 were distributed to the Immunological Synapse (IS) and perturbed expression of PRL-1 or PRL-2 by CRISPR/Cas9 mediated genome editing showed that the PRLs were required for proper distribution of WDR1 to filamentous (F)-actin at the IS. Further, perturbed expression of the PRLs or WDR1 resulted in defective IS assembly with deregulated F-actin rearrangements, altered positioning of LFA-1, and reduced IL-2 production. Interestingly, balanced expression of PRLs was required for accumulation of CD3{varepsilon} at the IS and early activating signalling. We propose that PRLs regulate early T cell signalling and are required for proper F-actin dynamics by regulating the WDR1 access to F-actin networks. As a consequence, PRLs regulate LFA-1 positioning at the IS and proper cytokine secretion.

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Aguilar-Sopena, O., Carrasco-Padilla, C., Gomez-Moron, A., Castro-Sanchez, P., Estaras-Hermosel, M., Valvo, S., Alegre-Gomez, S., Redondo-Munoz, J., Torres, R., Rodriguez-Perales, S., Ismail, S., Sanchez-Madrid, F., Martin-Cofreces, N. B., Dustin, M. L., Navarro, P. R.. 2023-12-28. Phosphatases of regenerating liver balance F-actin rearrangements during T cell activation through WD repeat containing protein 1. https://doi.org/10.1101/2023.12.28.573244

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