Investigating the cellular roles of LITAF and CDIP1

UoM administered thesis: Phd

  • Authors:
  • Wenxia Qin

Abstract

Mutations in LPS-Induced TNF Activating Factor/Small Integral Membrane Protein of the Late Endosome (LITAF/SIMPLE) cause Charcot-Marie-Tooth (CMT) type 1C disease, an autosomal-dominant demyelinating disorder of the peripheral nervous system. The pathogenesis has not been characterized due to little knowledge about the cellular roles of LITAF. N-terminus of LITAF contains PPXY and P(T/S)AP motifs that interact with E3 ubiquitin ligase Itch/Nedd4 and ESCRT-I subunit TSG101, respectively. C-terminus of LITAF consists of a hydrophobic region bracketed by two proposed "CXXC" zinc knuckles, termed the LITAF-like domain or the SIMPLE-like domain (SLD). Mammalian cells also express an uncharacterized Cell Death Inducing P53 target 1 (CDIP1), which has conserved PPXY and P(T/S)AP motifs as well as the LITAF-like domain. Here, we show that LITAF/CDIP1 belong to a novel class of monotopic integral membrane proteins and localise to multiple endocytic compartments. LITAF/CDIP1 are associated with EGFR-containing endosomes and also interact with HD-PTP. Knockdown of LITAF and CDIP1, affect the morphogenesis of Multivesicular Bodies (MVBs). We also show that LITAF (SLD) localises to the Tubular recycling endosome (TRE). LITAF/CDIP1 depletion cause expanded TRE which is involved in the recycling of Clathrin-independent cargoes. Introducing disease-linked mutations into the LITAF (SLD) abolished its TRE association. Hence, our study proposes that the CMT1C disease is caused due to the malformation of TRE and MVBs.

Details

Original languageEnglish
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Award date31 Dec 2016