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Rab10-CAV1 mediated intraluminal vesicles transport to migrasomes

ABSTRACT: Migrasomes, vesicular organelles generated on the retraction fibers of migrating cells, play a crucial role in migracytosis, mediating intercellular communication. The content cargoes determine the functional specificity of migrasomes. Migrasomes harbor numerous intraluminal vesicles, a pivotal component of their cargo. The mechanism underlying the transportation of these intraluminal vesicles to the migrasomes remain enigmatic. In this study, we identified a pathway by which Rab10-Caveolin1 mediates the transport of intraluminal vesicles to migrasomes. This intricate process necessitates the coordination of the motor protein Myosin Va, adaptor proteins RILPL2, facilitating vesicle transportation through retraction fibers to the migrasomes. Notably, the phosphorylation of Rab10 by the kinase LRRK2 augments this transport. Moreover, CSF-1 is selectively transported to migrasomes through this mechanism, subsequently fostering monocyte-macrophage differentiation in skin wound healing, which adds to our understanding of the physiological role of migrasomes.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yang Chen

PROVIDER: PXD046146 | iProX | Sat Oct 14 00:00:00 BST 2023

REPOSITORIES: iProX

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Project description:Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by compromised function of the neuromuscular junction (NMJ), manifesting with fatigable muscle weakness. Mutations in MYO9A were previously identified as causative for CMS but the precise pathomechanism remained to be characterised. Based on the role of MYO9A as a negative regulator of RhoA and an actin-based molecular motor, loss of MYO9A was hypothesised to affect the neuronal cytoskeleton, thus leading to impaired vesicular protein transport within the neuron. MYO9A-depleted NSC-34 cells (mouse motor neuron-derived cells) were used to assess the effect on the cytoskeleton revealing altered expression of a number of cytoskeletal proteins important for neuronal cell structure and intracellular transport. Based on these findings, the effect on vesicular protein transport was determined using a vesicular recycling assay revealing impaired recycling of neuronal relevant growth factor receptor. In addition, an unbiased approach utilising proteomic profiling of control and MYO9A-depleted NSC-34 cells was utilised to identify key players of the pathophysiology. Proteomic data support a role for defective vesicular transport and identified affected proteins which are also involved in the manifestation of other neuromuscular disorders. Prompted by the clear indication of perturbed protein transportation, further proteomics-based secretomic analysis of NSC-34 cells have been performed to identify whether secretion is similarly affected. Indeed, this led to the identification of a potential therapeutic target, agrin. Zebrafish lacking MYO9A orthologues (myo9aa/ab) were treated with "Agrin Biologic", an agrin compound, and amelioration of defects in neurite extension and in movement of the zebrafish was observed. Our combined data not only allow new insights into the pathophysiology of CMS and show that loss of MYO9A affects the neuronal cytoskeleton, leading to impaired transport and vesicular recycling of proteins, but on a more general note also represent a successful biomedical approach: from the identification of the underlying pathomechanism to the definition of a therapeutic intervention concept.

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Rab10-CAV1 mediated intraluminal vesicles transport to migrasomes

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