Scientists from the Biozentrum of the University of Basel report that they have discovered a cellular machine, called FERARI, that sorts out usable proteins for recycling. In Nature Cell Biology, they explain how FERARI works and why it is so special (“FERARI is required for Rab11-dependent endocytic recycling”).

“Endosomal transport is essential for cellular organization and compartmentalization and cell–cell communication. Sorting endosomes provide a crossroads for various trafficking pathways and determine recycling, secretion or degradation of proteins. The organization of these processes requires membrane-tethering factors to coordinate Rab GTPase function with membrane fusion,” write the investigators.

“Here, we report a conserved tethering platform that acts in the Rab11 recycling pathways at sorting endosomes, which we name factors for endosome recycling and Rab interactions (FERARI). The Rab-binding module of FERARI consists of Rab11FIP5 and rabenosyn-5/RABS-5, while the SNARE-interacting module comprises VPS45 and VIPAS39. Unexpectedly, the membrane fission protein EHD1 is also a FERARI component. Thus, FERARI appears to combine fusion activity through the SM protein VPS45 with pinching activity through EHD1 on SNX-1-positive endosomal membranes. We propose that coordination of fusion and pinching through a kiss-and-run mechanism drives cargo at endosomes into recycling pathways.”

How exactly the endosomes sort the material remains an enigma. A research team led by Anne Spang, PhD, has now discovered that FERARI is a key player in this process. FERARI distributes the recyclable molecules, mainly transport proteins and receptors, and reintroduces them into the cellular cycle. In this way, valuable cell components do not have to be constantly produced anew, which not only saves energy but also time.

Endosomes are small membrane-bound vesicles inside animal and plant cells. During their maturation, endosomes pass through various stages in which they carry out different tasks. The early endosomes mainly absorb material, the more mature ones sort out the recyclable material and the late endosomes dispose of the non-reusable residual waste. In the sorting endosomes, the researchers have now demonstrated that FERARI acts as a kind of distribution platform. “FERARI consists of different proteins and is responsible for ensuring that vesicles, used for recycling, dock onto the sorting endosomes and can be loaded with reusable material,” explains Spang.

The special feature of FERARI is that it coordinates both the fusion of the endosome with the recycling vesicle as well as the pinching off of the recycling vesicle after it has been loaded with the cargo. The loaded vesicles then transport their cargo to the site of action, the cell membrane. “Our work contradicts the current thinking which assumes that all recycling vesicles are pinched off directly from the endosome,” says Spang. “We are the first to show this kind of ‘kiss-and-run’ mechanism.”

If FERARI does not work properly, recycling in the cell is impaired. Disorders in cellular transport and recycling processes can lead to a variety of diseases, including cancer, metabolic and neurodegenerative diseases.

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