03 February 2023
Helping cells keep molecular cargo on the right track
Published online 19 October 2022
Insights into cellular traffic management could have important implications for diseases driven by malfunctions in this process.
The cellular interior is crisscrossed with protein fibres known as microtubules, which serve as highways for the trafficking of important biomolecular cargos. A team led by George Shubeita, at New York University Abu Dhabi, has uncovered an important mechanism governing the flow of this traffic, which could contribute to the metastatic growth behaviour of cancer cells.
The physical labour of intracellular trafficking is performed by two motor proteins known as dynein and kinesin, which respectively convey payloads deeper into the cellular interior, or towards the outer plasma membrane. However, the higher-level regulatory networks governing these motors are poorly understood, and Shubeita and colleagues set out to learn more about this process.
The researchers focused on a protein called MAP4, which belongs to a larger family of microtubule-associated proteins (MAPs). Past studies have shown that MAP4 can interfere with cargo transport, and it has generally been assumed that these effects are mediated exclusively based on MAP4’s effects on the microtubule fibres themselves.
But Shubeita’s team uncovered surprising new details about MAP4 function, painting a more complex picture. They determined that in addition to binding to the microtubules, activated MAP4 also makes direct contact with the cargoes themselves, as well as the dynein motor proteins that convey those payloads along the microtubule. This interaction creates a bias in the flow of traffic, and cells with elevated MAP4 activity exhibited increased delivery of mitochondria—the cell’s energy-generating organelle—to the region surrounding the nucleus. “MAP4 reduces the ability of the kinesin motor to generate the force needed to sustain organelle transport away from the nucleus,” says Shubeita.
These findings could highlight an important and previously unappreciated regulatory function of MAPs as a general class of proteins, according to Adam Hendricks, who studies motor proteins at McGill University in Canada. “This work adds to the growing evidence that many MAPs regulate motor proteins not by simply altering the microtubule track, but by directly interacting with the motors,” he says.
Since efficient cargo management is essential for cellular health, these findings could have important implications for a range of diseases. In the present work, for example, Shubeita and colleagues outline a mechanism by which certain cancer therapies could inadvertently promote metastasis by interfering with MAP4-mediated organelle trafficking—driving invasion by redirecting mitochondria to the cellular edge rather than the interior. “We are now in the process of establishing a direct role for MAP4,” says Shubeita.
Nabti, I. et al. The ubiquitous microtubule-associated protein 4 (MAP4) controls organelle distribution by regulating the activity of the kinesin motor. Proc. Natl. Acad. Sci. U.S.A. 119, e2206677119 (2022).