title: Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type  1C Mutation of SIMPLE Protein.
abstract: Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along with endosomal sorting complex required for transport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs punctain late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor , prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-κB and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Xuelian
authors.initials: X
authors.lastname: Zhao
authors.forename: Deborah
authors.initials: D
authors.lastname: Brancho
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Liang
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Zou
authors.forename: Craig
authors.initials: C
authors.lastname: Bennett
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000166:cytology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D057146:Multivesicular Bodies / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C492727:Litaf protein, mouse; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate