Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.

Blerida Banushi,Mark Marsh,Gema Ariceta,Federico Forneris,Danai Bem,Laurent Bozec,Chunguang Wang,Kevin Mills,Francesco Ferraro,Jemima J Burden,Clare Rogerson,Ivan Doykov,Maija Risteli,Simon N Waddington,Mark Girolami,Paul Gissen,Julita Latka-Grot,Adam Strange,Asllan Gjinovci,Marcin Zaniew,Anna Straatman-Iwanowska,Joanna Hanley,Scott P Lawrence ,R Ardill ,Stewen J Howe ,János Kriston-Vizi ,K.r Straatman ,Anne Marie Lyne ,H R Smith ,Wendy Heywood

doi:10.1038/ncomms12111

Abstract

Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. However, the mechanism and contribution of collagen modifications that occur outside the endoplasmic reticulum and Golgi are not understood. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types. Identification of structural and functional collagen abnormalities in cells and tissues from patients and murine models of the autosomal recessive multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome caused by VIPAR and VPS33B deficiencies confirmed our findings. Thus, regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues.

Highlights

IntroductionPost-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function
Post-translational modifications are necessary for collagen precursor molecules to acquire final shape and function
Since previous data suggested that VPS33B and VIPAR in complex regulate apical–basolateral polarity and may act as an effector for RAB11A associated with recycling endosomes[20], we examined whether RAB11A, RAB25 and RAB10 proteins are required for LH3 delivery to Collagen IV Carriers (CIVC) because of their involvement in recycling endosome function and in apical–basolateral polarity regulation[31,32,33]

Summary

Introduction

Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types. Identification of structural and functional collagen abnormalities in cells and tissues from patients and murine models of the autosomal recessive multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome caused by VIPAR and VPS33B deficiencies confirmed our findings. Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues. Structural defects in collagen I are found in tail tendons from VPS33B- and VIPAR-deficient mice Taken together, these findings establish a role for VPS33B/VIPAR in the intracellular trafficking of LH3 and collagen homeostasis

Methods

Results

Conclusion