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Published on: July 5, 2019
Distinct structural domains within C19ORF5 support association with stabilized microtubules and mitochondrial
Leyuan Liu1, Amy Vo, Guoqin Liu
1Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.
Abstract:
C19ORF5 is a sequence homologue of microtubule-associated proteins MAP1A/MAP1B of unknown function, except for its association with mitochondria-associated proteins and the paclitaxel-like microtubule stabilizer and candidate tumor suppressor RASSF1A. Here, we show that when overexpressed in mammalian cells the recombinant 393-amino acid residue COOH terminus of C19ORF5 (C19ORF5C) exhibited four types of distribution patterns proportional to expression level. Although normally distributed throughout the cytosol without microtubular association, C19ORF5C specifically accumulated on stabilized microtubules in paclitaxel-treated cells and interacted directly with paclitaxel-stabilized microtubules in vitro. The native 113-kDa full-length C19ORF5 and a shorter 56-kDa form similarly associated with stabilized microtubules in liver cells and stabilized microtubules from their lysates. As C19ORF5 accumulated, it appeared on mitochondria and progressively induced distinct perinuclear aggregates of mitochondria. C19ORF5 overlapped with cytochrome c-deficient mitochondria with reduced membrane potential. Mitochondrial aggregation resulted in gross degradation of DNA, a cell death-related process we refer to as mitochondrial aggregation and genome destruction (MAGD). Deletion mutagenesis revealed that the C19ORF5 hyperstabilized microtubule-binding domain resides in a highly basic sequence of <100 residues, whereas the MAGD activity resides further downstream in a distinct 25-residue sequence (F967-A991). Our results suggest that C19ORF5 mediates communication between the microtubular cytoskeleton and mitochondria in control of cell death and defective genome destruction through distinct bifunctional structural domains. The accumulation of C19ORF5 and resultant MAGD signaled by hyperstabilized microtubules may be involved in the tumor suppression activity of RASSF1A, a natural microtubule stabilizer and interaction partner with C19ORF5, and the taxoid drug family.
Insights
C19ORF5 protein interacts with stabilized microtubules and mitochondria, inducing cell death via mitochondrial aggregation and genome destruction (MAGD). This process may contribute to tumor suppression, linking microtubule dynamics to cell fate.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- C19ORF5 is a microtubule-associated protein homologue with unknown function.
- It associates with mitochondria-associated proteins and RASSF1A, a microtubule stabilizer and tumor suppressor.
- Previous studies indicated its potential role in cellular processes but lacked functional characterization.
Purpose of the Study:
- To investigate the function and cellular localization of C19ORF5.
- To elucidate the mechanism by which C19ORF5 influences cell death pathways.
- To identify the functional domains responsible for C19ORF5's activities.
Main Methods:
- Overexpression of C19ORF5 C-terminus in mammalian cells.
- Analysis of protein localization using microscopy in response to paclitaxel.
- In vitro interaction assays with stabilized microtubules.
- Deletion mutagenesis to identify functional domains.
- Assessment of mitochondrial function and DNA degradation.
Main Results:
- C19ORF5C accumulates on stabilized microtubules and interacts with them in vitro.
- C19ORF5 induces perinuclear mitochondrial aggregation, leading to cytochrome c deficiency and reduced membrane potential.
- Mitochondrial aggregation triggers DNA degradation, a process termed MAGD.
- Distinct domains within C19ORF5 mediate microtubule binding and MAGD activity.
Conclusions:
- C19ORF5 acts as a bridge between the microtubule cytoskeleton and mitochondria.
- It controls cell death through a novel mechanism (MAGD) involving mitochondrial dysfunction.
- C19ORF5's bifunctional domains and MAGD activity may contribute to RASSF1A's tumor suppressor function and taxoid drug effects.
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