Mycobacterial Sulfoglycolipid-1 is a novel regulator of host actin dynamics

Pathogens harbour a variety of strategies for channelizing the host molecular machinery to facilitate their entry and pathogenesis. Host cytoskeleton has emerged as most exploited host component, however the underlying mechanisms are less studied. Here using quantitative microscopy-based techniques, we revealed mycobacterial sulfoglycolipid, SL-1, to alter the interaction landscape between the host plasma membrane, phosphatidylinositol lipids, and F-actin. The changed abundance and dispersion of phosphoinositides and F-actin further impact their interactions with essential cytoskeletal proteins such as Arp2/3, N-WASP, cofilin, vinculin, and talin involved in actin assembly and disassembly. We show that SL-1 reduces cholesterol-rich plasma membrane domains and sequesters phosphoinositides into de novo lipid domains, boosting interactions with actin at the plasma membrane, but phosphoinositide shielding reduces interactions with actin-binding proteins. The most noteworthy is the diminished interactions between cofilin with both phosphoinositide lipid and F-actin coupled with reduction of ADP-ribosylation factor (Arf) GTPase-activating proteins thus initiating actin fragmentation in ASAP-1 dependent fashion. This phenotype fosters higher bacterial uptake within the host and modulates cell migration by altering actin alignment and filopodia dynamics. Collectively, our findings highlight potential key molecular events and players involved in host cytoskeleton remodelling upon exposure to mycobacterial lipids during tubercular infection that enhances bacterial uptake within the host.