Proteomic Identification of Cytokeratin 19 Association with Retromer Reveals a Connection with Cellular Dynamics

TL;DR

This study shows that retromer, a protein complex involved in cell trafficking, interacts with cytokeratin 19 and plays a role in cell division and migration.

Contribution

The novel finding is the association of retromer with cytokeratin 19 and its involvement in cellular dynamics during division and migration.

Findings

Retromer interacts with cytokeratin 19 and localizes to the pericentriolar region during cell division.

Retromer depletion disrupts cytokeratin 19 localization and affects post-metaphase progression and cell migration.

The study links retromer to key cellular processes like cytokinesis and epithelial cell movement.

Abstract

Retromer is an evolutionarily conserved protein complex first identified in budding yeast. It was originally described for its essential role in endosome-to-Golgi retrieval of lysosomal hydrolase receptors. Retromer is now known to mediate trafficking of many endosomal cargoes. The mammalian retromer is constituted by a core heterotrimer encoded by the vacuolar protein sorting (VPS) gene products VPS26, VPS35, and VPS29. To mediate cargo recognition and endosomal sorting into various pathways, this trimer can cooperate with phosphoinositide-binding sorting nexin family members. Defective retromer functioning has been associated with alterations in cellular homeostasis, leading to disease. To gain insights into how it may mediate these broad processes, a proteomic strategy in polarized Madin-Darby canine kidney cells was devised to identify retromer-interacting proteins. Subsequent validation of one of the candidates, i.e., cytokeratin 19, led to the unexpected finding that retromer localizes to the pericentriolar region in dividing cells and subsequently translocates to the midbody during cytokinesis. Retromer was found interacting with CK19, and its antisense depletion led to delocalization from CK19. Subcellular fractionation and live cell monitoring of depleted cells provided evidence of a role by retromer in post-metaphase progression and in epithelial cell migration, thereby connecting retromer with key processes of cellular dynamics.

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