TMEDs mediate versatile cargo transport in vesicle-dependent unconventional secretion

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Unconventional protein secretion (UcPS) exports proteins lacking signal peptides, but its cargo selectivity mechanisms are unclear.
• Understanding UcPS is crucial for various cellular processes and diseases involving protein export.

Purpose of the Study:

• To identify key regulators of cargo selectivity in vesicle-dependent unconventional protein secretion.
• To elucidate the molecular mechanisms by which TMED proteins mediate selective cargo translocation.

Main Methods:

• Investigated the role of TMED proteins in UcPS using biochemical assays and cellular imaging.
• Analyzed TMED protein oligomerization states and their impact on cargo translocation.
• Examined the importance of the ER-Golgi intermediate compartment (ERGIC) in TMED-mediated secretion.

Main Results:

• TMED proteins act as translocators, facilitating cargo passage across membranes with HSP90 assistance and partial unfolding.
• Cargo selectivity is determined by TMED cytoplasmic tail binding to specific cargoes during translocation.
• TMED homo-oligomerization, promoted by ERGIC localization and cargo binding, enhances translocation efficiency.
• TMED hetero-tetramerization was found to inhibit translocation.

Conclusions:

• TMED proteins are central regulators of cargo diversity in UcPS.
• TMED oligomerization state and ERGIC localization are critical for modulating translocation efficiency and cargo selection.
• This study reveals a novel feed-forward mechanism controlling UcPS.