Deep inside the human body, a protein named TM184C has been hiding in plain sight — and it helps cells reach across tiny bridges to share energy and materials with their neighbors. Scientists had never really studied it, because they were looking for the wrong things.
For decades, researchers explored proteins by comparing their genetic sequences, the genetic codes that build them. A team at the Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, tried something different: they used artificial intelligence to compare the three-dimensional shapes of more than 214 million predicted proteins. Shape matters because a protein's form often reveals what it does.
"We wanted to know what biology we might be missing if we searched by three-dimensional structure instead," said study senior author Daniel G. Isom, Ph.D. "What we found suggests there is another layer of biology that has been hiding in plain sight."
That search turned up TM184C, a protein that looks like a member of the GPCR family — a group that helps cells sense and respond to signals from outside. But TM184C behaves differently. Much of it lives deep inside the cell, within the membranes of tiny packages called vesicles that carry materials around.
The researchers found these vesicles travel along the cell's internal highways, called microtubules, and gather in thin projections that connect neighboring cells. Those projections act like bridges. Through them, cells exchange metabolites, vesicles, and even organelles — including mitochondria, the energy-producing powerhouses of the cell.
"When we saw TM184C-positive vesicles moving through connections between cells, we realized these structures could be routes for substantial material exchange," said Jenniffer Arcuri, Ph.D., a senior scientist at Sylvester and the study's lead author. "That completely changed how we thought about TM184C."
When researchers disrupted TM184C, cells formed fewer connections and showed changes in shape, showing the protein helps build and manage these intercellular conduits.
The discovery raises a fascinating question: when cells share resources, who benefits? In healthy tissue, this exchange may help cells survive stress by moving fuel or damaged components where they're needed. In cancer, where tumor cells often grow short of oxygen and nutrients, these bridges could give some cells another way to survive by drawing support from their surroundings.
Graduate student Bruno Colon, studying these connections in normal cells and aggressive cancers like glioblastoma, sees a potential opening: "Understanding their role could give us new insight into how these tumors communicate and potentially reveal vulnerabilities we haven't recognized before."
TM184C also helps regulate autophagy — the process cells use to break down and recycle old parts. When the protein was reduced, markers of this recycling process increased. The team even tested a similar yeast protein, Hfl1; removing it caused problems in yeast, but adding the human TM184C fixed them — a surprising sign that this function has been conserved across vast stretches of evolution.
The findings, published in the journal Nature, open a new way to study how cells communicate, survive stress, and possibly contribute to disease — biology that has been hiding in plain sight all along.