Spatiotemporal Control of Actomyosin Contractility by MRCKβ Signaling Drives Phagocytosis

Zihni, C.; Georgiadis, T.; Ramsden, C.; Sanchez-heras, E.; Nommiste, B.; Semenyuk, O.; Bainbridge, J.; Coffey, P.; Smith, A.; Ali, R.; Balda, M.; Matter, K.

doi:10.1101/2021.03.25.436833

bioRxiv · 10.1101/2021.03.25.436833

Spatiotemporal Control of Actomyosin Contractility by MRCKβ Signaling Drives Phagocytosis

Zihni, C.·Georgiadis, T.·Ramsden, C.·Sanchez-heras, E.·Nommiste, B.·Semenyuk, O.·Bainbridge, J.·Coffey, P.·Smith, A.·Ali, R.·Balda, M.·Matter, K.

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Abstract

Phagocytosis requires myosin-generated contractile force to regulate actin dynamics. However, little is known about the molecular mechanisms that guide this complex morphodynamic process. Here we show that particle binding to Mer Tyrosine Kinase (MerTK), a widely expressed phagocytic receptor, stimulates phosphorylation of the Cdc42 GEF Dbl3 in the retinal pigment epithelium (RPE), triggering activation of MRCK{beta} and its co-effector N-WASP that cooperate to deform the membrane into cups. Continued MRCK{beta} activity then drives recruitment of a mechanosensing bridge enabling transmission of the cytoskeletal force required for cup closure and particle internalization. MRCK{beta} is also required for Fc receptor-mediated phagocytosis by macrophages. In vivo, MRCK{beta} is essential for RPE phagocytosis of photoreceptor debris and, hence, retinal integrity. MerTK-independent activation of MRCK{beta} signaling by a phosphomimetic Dbl3 mutant rescues phagocytosis in retinitis pigmentosa RPE cells lacking functional MerTK. Thus, conserved MRCK{beta} signaling controls spatiotemporal regulation of actomyosin contractility to guide actomyosin dynamics-driven phagocytosis and represents the principle phagocytic effector pathway downstream of MerTK.

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Zihni, C., Georgiadis, T., Ramsden, C., Sanchez-heras, E., Nommiste, B., Semenyuk, O., Bainbridge, J., Coffey, P., Smith, A., Ali, R., Balda, M., Matter, K.. 2021-03-25. Spatiotemporal Control of Actomyosin Contractility by MRCKβ Signaling Drives Phagocytosis. https://doi.org/10.1101/2021.03.25.436833

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