Diverse cellular processes are driven by motor proteins that are recruited to and generate force on lipid membranes. Surprisingly little is known about how membranes control the force from motors and how this may impact specific cellular functions. Here, we show that dynein motors physically cluster into microdomains on the membrane of a phagosome as it matures inside cells. Such geometrical reorganization allows many dyneins within a cluster to generate cooperative force on a single microtubule. This results in rapid directed transport of the phagosome toward microtubule minus ends, likely promoting phagolysosome fusion and pathogen degradation. We show that lipophosphoglycan, the major molecule implicated in immune evasion of Leishmania donovani, inhibits phagosome motion by disrupting the clustering and therefore the cooperative force generation of dynein. These findings appear relevant to several pathogens that prevent phagosome-lysosome fusion by targeting lipid microdomains on phagosomes.
Bibliographical noteFunding Information:
R.M. acknowledges funding through an International Senior Research Fellowship from the Wellcome Trust UK (grant WT079214MA) and a Wellcome Trust – Department of Biotechnology Senior Fellowship (grant IA/S/11/2500255). We thank K. Verhey, M. Koonce, T. Hyman, and D. Bhattacharya for sharing reagents. We also thank S.J. Turco and S. Roy for sharing LPG (originally prepared by S.J. Turco). We acknowledge A. Dsouza, R. Jha, and T. Kapoor for help with experiments. We thank A. Chattopadhyay, Arpan Rai, P. Barak, and V. Soppina for comments on the manuscript. We thank S. Mayor for comments and criticism on the manuscript. We acknowledge the mass spectrometry facilities at NCBS and C-CAMP (Bengaluru).