Remarkably little is known about M cells, which reside in the intestine and participate in immune surveillance of potential pathogens. However, Hiroshi Ohno was taken aback when Koji Hase, a staff scientist in his laboratory at the RIKEN Center for Allergy and Immunology in Yokohama, identified a highly active M cell gene that triggered the formation of unusually long and thin membrane projections when expressed in other cell types.
“I thought it was an artifact,” recalls Ohno, “but Koji insisted on its importance.” Subsequent experiments proved Hase correct; a mammalian protein called M-Sec appears to drive formation of an enigmatic class of intercellular connections known as ‘tunneling nanotubes’ (TNT). TNTs are known to participate in the trafficking of a variety of cargoes, ranging from ions to proteins to cargo-laden membrane vesicles—and, less beneficially, viruses and prions. However, these findings offer the first real insights into the underlying mechanisms of TNT growth1.
In a series of experiments using mouse immune cells known as macrophages that also express endogenous M-Sec, Ohno’s group showed that formation of TNTs was inhibited upon knockdown of M-Sec expression. These TNTs were also shown to be physiologically active, enabling signals to be transmitted from cell to cell via the movement of calcium ions.
Cells rely on a protein-based framework known as the cytoskeleton to provide infrastructure, and major morphological changes typically involve cytoskeletal rearrangements mediated by molecular switches known as small GTPases. Ohno and colleagues found that M-Sec associates with RalA, a small GTPase, and a membrane-bound protein complex known as the exocyst, and that these interactions are essential to the formation and growth of membrane protrusions that will ultimately form TNTs.
The researchers are now delving deeper into the bigger picture of M-Sec function by studying mice that have been genetically engineered to lack this protein, but are also exploring more direct ways to target M-Sec activity. “We have started screening M-Sec-binding small-molecular-weight chemicals that could inhibit M-Sec-mediated TNT formation,” says Ohno.
He suggests that such drugs could ultimately be used in vivo to block the transmission of viruses via these intercellular conduits, but sees the most immediate benefits in simply understanding why these connections exist in the first place. “Virtually nothing is known about their in vivo relevance,” he says. “In this regard, the discovery of M-Sec as a promoter of TNT formation will accelerate the understanding of their physiological role.”
The corresponding author for this highlight is based at the Laboratory for Epithelial Immunobiology, RIKEN Research Center for Allergy and Immunology
