Dysregulated inflammatory signaling upon Charcot-Marie-Tooth type 1C mutation of SIMPLE protein

Wenjing Li, Hong Zhu, Xuelian Zhao, Deborah Brancho, Yuanxin Liang, Yiyu Zou, Craig Bennett, Chi Wing Chow

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 puncta in 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 β, 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.

Original languageEnglish (US)
Pages (from-to)2464-2478
Number of pages15
JournalMolecular and Cellular Biology
Volume35
Issue number14
DOIs
StatePublished - 2015

Fingerprint

Multivesicular Bodies
Tooth
Endosomes
Endosomal Sorting Complexes Required for Transport
Mutation
Sequence Deletion
Ubiquitin
Proteins
TNF Receptor-Associated Factor 6
MAP Kinase Kinase 4
Poisons
Transforming Growth Factors
Ligases
Chemokines
Carrier Proteins
Phosphorylation
Cytokines
Ligands
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Dysregulated inflammatory signaling upon Charcot-Marie-Tooth type 1C mutation of SIMPLE protein. / Li, Wenjing; Zhu, Hong; Zhao, Xuelian; Brancho, Deborah; Liang, Yuanxin; Zou, Yiyu; Bennett, Craig; Chow, Chi Wing.

In: Molecular and Cellular Biology, Vol. 35, No. 14, 2015, p. 2464-2478.

Research output: Contribution to journalArticle

Li, Wenjing ; Zhu, Hong ; Zhao, Xuelian ; Brancho, Deborah ; Liang, Yuanxin ; Zou, Yiyu ; Bennett, Craig ; Chow, Chi Wing. / Dysregulated inflammatory signaling upon Charcot-Marie-Tooth type 1C mutation of SIMPLE protein. In: Molecular and Cellular Biology. 2015 ; Vol. 35, No. 14. pp. 2464-2478.
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