Linstedt and Mukhopadhyay discovered exactly how Shiga toxin avoided the lysosome as they were doing basic biological research to understand how components of the cell function. "If we weren't focused on answering fundamental biological questions, we wouldn't have made this discovery," Linstedt said.
Fifteen years ago Linstedt discovered GPP130, a protein found in the Golgi apparatus, a kind of post office for the cell that sorts and packages molecules made in the endoplasmic reticulum and delivers them to their final destinations within the cell. GPP130, Linstedt found, didn't behave like most Golgi proteins. Rather than remaining in the Golgi, GPP130 constantly cycles to the endosomes and back to the Golgi. As it returns, it avoids the pathway that takes a substance to the lysosome to be degraded.
In Science, Linstedt and Mukhopadhyay report that Shiga toxin exploits this unique quality of GPP130 to its advantage. As it starts its return to the Golgi, GPP130 moves into a tubular extension off of the endosome's membrane and avoids being sent to the degradation pathway. Shiga toxin binds to GPP130, hitching a ride on a route that doesn't go to the lysosome. Instead, the toxin is carried to the Golgi apparatus and then to the endoplasmic reticulum, where it gets released into the cell's cytoplasm. It's here that it does its damage, shutting down protein synthesis and causing the cell to die.
"I knew that Shiga toxin was one of the key cargo molecules that bypass the lysosome as they go from the endosome to the Golgi apparatus, so I figured it would be a good marker to study in relation to GPP130. What I didn't realize was how profoundly dependent Shiga toxin was on GPP130," Linstedt said.
But the most serendipitous aspect of this discovery can be traced to a phone call made four years ago. Don Smith, a
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Carnegie Mellon University