The time that transmembrane (TM) signaling receptors spend in the Golgi directly determines their maturation and, consequently, their efficiency in transmitting signals at the plasma membrane. How cells precisely control this residence time, preventing receptors from exiting too early or remaining too long, and whether specialized regulatory molecules control this process, have remained largely unclear.

In a study published in PNAS on January 23, researchers from the Institute of Biophysics of the Chinese Academy of Sciences and the Hong Kong University of Science and Technology revealed that LEPROT and LEPROTL1, a class of COPI cargo receptors, coordinate the transient retention of signaling receptors in the Golgi. This discovery unveils an unrecognized regulatory pathway for TM receptor maturation.

Through GLIM localization and knockout-rescue experiments, the researchers discovered that LEPROTs are primarily localized in the cis-medial Golgi, where they assist in maintaining the Golgi's structure. Biochemical interaction assays showed that LEPROTs directly bind to COPI coats via a conserved WxxW motif and rely on COPI-dependent mechanisms to remain in the Golgi.

The researchers then performed vesicle budding assays and mass spectrometry, identifying LEPROTs as COPI cargo receptors that co-package specific signaling receptors. Protein interaction analyses and RUSH trafficking experiments demonstrated that LEPROTs selectively recognize TM domains of appropriate length. This allows them to capture receptors at the trans-Golgi and release them at the cis-Golgi in a pH-dependent manner via COPI retrieval.

Functional studies revealed that this Golgi retention is critical for receptor maturation. Measurements of glycosylation, palmitoylation, signaling responses, and receptor localization showed that LEPROTs control TM receptor activity by promoting proper Golgi residency and post-Golgi modification.

This work provides the first direct evidence that COPI cargo receptors regulate the residence time of transmembrane (TM) signaling receptors along the anterograde endomembrane pathway (ER → Golgi → plasma membrane). It also expands the known functional scope of COPI cargo receptors. Previously, they were thought to primarily regulate Golgi-resident enzymes; however, this study shows that they directly influence the maturation and activity of signaling receptors.

These findings offer a new molecular framework for understanding how TM receptor trafficking is regulated and suggest potential strategies for modulating receptor activity in human diseases.

Schematic of LEPROTs regulating the modification of TM receptors (Image by HU Junjie's group)