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Toll-interacting protein pathway: degradation of an ubiquitin-binding protein
Miho Shimizu1, Asami Oguro-Ando2, Eri Ohoto-Fujita1
1Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan; Radioisotope Center, Cell to Body Dynamics Laboratory 1, The University of Tokyo, Tokyo, Japan.
Insights
Tollip protein protects neuronal cells from death caused by polyglutamine (polyQ) expansion in Huntington's disease (HD). This protein may serve as a sensor for polyQ toxicity by tracking protein aggregation and cellular transport pathways.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Neurodegenerative diseases like Huntington's disease (HD) stem from expanded CAG trinucleotide repeats (polyQ) in genes.
- A toxic gain of function from polyQ expansion is implicated in pathogenesis, leading to neuronal cell death via polyQ-expanded huntingtin (htt) aggregates.
- Tollip and Tom1 proteins interact with ubiquitin chains, suggesting a role in protein degradation pathways.
Purpose of the Study:
- To investigate the protective role of Tollip against polyQ-expanded htt toxicity in a cellular model of Huntington's disease.
- To explore Tollip's mechanism in recruiting misfolded proteins to aggresomes via the endosomal pathway.
- To establish a cell-based system for assessing protein involvement in Tollip-mediated pathways and its potential as a polyQ toxicity sensor.
Main Methods:
- Utilized a cellular model of Huntington's disease (HD) to study the effects of polyglutamine (polyQ) expansion.
- Investigated the interaction between Tollip, Tom1, and ubiquitinated protein aggregates.
- Examined Tollip's role in recruiting misfolded proteins to aggresomes through late endosome-mediated pathways.
Main Results:
- Demonstrated that Tollip significantly protects neuronal cells from the toxicity induced by polyQ-expanded huntingtin (htt).
- Confirmed Tollip's protective effect against cell death in the HD cellular model.
- Showed that Tollip recruits misfolded proteins to aggresomes via late endosomes, involving microtubule-dependent trafficking.
Conclusions:
- Tollip plays a crucial protective role against polyQ-induced neurotoxicity, particularly in Huntington's disease.
- Tollip functions within a cellular pathway involving protein aggregation, degradation, and trafficking.
- The Tollip pathway offers a potential system for sensing polyQ toxicity and evaluating protein involvement in cellular homeostasis mechanisms like autophagy and ERAD.
Abstract:
The nine neurodegenerative disorders including Huntington disease (HD) are caused by the expansion of a trinucleotide CAG repeats (polyQ), which are located within the coding of the affected gene. Previous studies suggested that a gain of toxic function by polyQ repeats is widely thought to have a major role in pathogenesis. PolyQ-expanded htt induced ubiquitinated aggregates cause cell death in neuronal cells. Using a HD cellular model, we demonstrate that Tollip protects cells against the toxicity of polyQ-expanded htt and also protects cells from death (Oguro, Kubota, Shimizu, Ishiura, & Atomi, 2011). Tom1 which belongs to the VHS domain-containing protein family is also found to be directly binding to ubiquitin chains and Tollip (Katoh et al., 2004; Yamakami, Yoshimori, & Yokosawa, 2003). Tollip recruits misfolded protein to aggresome via late endosome. The cell system can be used to determine if your protein of interest is controlled under a part of Tollip pathway or not among other cell homeostatic systems: molecular chaperons, autophagy, and endoplasmic reticulum (ER)-associated degradation (ERAD). Tollip can be used for polyQ cell toxicity sensor by detecting microtubule-dependent trafficking and aggresome colocalization of aggregated protein.
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