Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Abstract

An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)-Hook-FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-enddirected microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state.Rab5 | FHF complex | dynein | neuronal polarity | retrograde transport N eurons are highly polarized cells with distinct somatodendritic and axonal domains. Synaptic inputs are received through the somatodendritic domain, integrated at the axon initial segment (AIS), and propagated along the axon for transmission to downstream cells. To accomplish these specialized functions, each neuronal domain is endowed with a distinct set of proteins. A fundamental but still largely unanswered question is how neurons establish and maintain this polarized distribution of proteins throughout their lifetimes. The available evidence indicates that the mechanisms of polarized sorting in neurons are quite complex (1-3). Newly synthesized transmembrane proteins travel together from their site of synthesis in the rough endoplasmic reticulum (ER) to the Golgi complex. Once they reach the trans-Golgi network (TGN), the proteins are sorted into different membraneenclosed transport carriers destined for the somatodendritic or axonal domains (4-8). However, the efficiency of this biosynthetic sorting varies for different proteins and is often incomplete. Other processes, such as compartment-specific retention, retrieval, or transcytosis, additionally contribute to establishing the overall distribution of proteins between the somatodendritic and axonal domains and to their localization to specialized subdomains (5, 9-17).The selective incorporation of transmembrane proteins into specialized transport carriers is a key event in the mechanisms of polarized sorting. In some cases this process is mediated by recognition of sorting signals in the cytosolic tails of the proteins by components of protein coats associated with the cytosolic face of the donor compartment. One of the best-documented examples is the sorting of various transmembrane proteins to the somatodendritic domain...

CDK5‐dependent activation of dynein in the axon initial segment regulates polarized cargo transport in neurons

“…These changes in TfR trafficking upon inhibition or depletion of CDK5 indicate a critical role for kinase in the regulation of sorting at the AIS, but do not preclude the involvement of other regulatory mechanisms for dynein within the AIS. 46,47 …”

Fungal Morphogenesis, from the Polarized Growth of Hyphae to Complex Reproduction and Infection Structures

“…Minus-end-directed transport is conducted by cytoplasmic dynein, whose activity is regulated by the dynactin and FHF complex (FTS/Hook/FHIP) (163). Whereas kinesin-3 contains a pleckstrin homology domain for interactions with endosomal lipids (166,167), components of the FHF complex interact with Rab5 to connect dynein to early endosomes (163,168).…”

Moving and positioning the endolysosomal system

“…1). Centripetal transport of EEs, for example, is mediated by Rab5 and the Rab5-effector FHF complex, composed of FHIP, Hook and FTS subunits [16,17,18,19,20]. FHIP is the subunit that directly interacts with Rab5 [20], whereas Hook simultaneously binds to dynein and dynactin, stabilizing this complex and enhancing the processivity of transport [21,22].…”