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Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a

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Abstract

ISG12a is one of the most highly induced genes following treatment of cells with type I interferons (IFNs). The encoded protein belongs to a family of poorly characterized, low molecular weight IFN-inducible proteins that includes 6–16 (G1P3), 1–8U (IFITM3), and 1–8D (IFITM2). Our studies demonstrate that the ISG12a protein associates with or inserts into the mitochondrial membrane. Transient expression of ISG12a led to decreased viable cell numbers and enhanced sensitivity to DNA-damage induced apoptosis, effects that were blocked by Bcl-2 co-expression or treatment with a pan-caspase inhibitor. ISG12a enhanced etoposide induced cytochrome c release, Bax activation and loss of mitochondrial membrane potential. siRNA-mediated inhibition of ectopic ISG12a protein expression prevented the sensitization to etoposide-induced apoptosis and also decreased the ability of IFN-β pretreatment to sensitize cells to etoposide, thereby demonstrating a role for ISG12a in this process. These data suggest that ISG12a contributes to IFN-dependent perturbation of normal mitochondrial function, thus adding ISG12a to a growing list of IFN-induced proteins that impact cellular apoptosis.

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Abbreviations

IFITM:

IFN inducible transmembrane protein

IFN:

Interferon

ISG:

IFN-stimulated gene

Mtch:

Mitochondrial carrier homolog

PVDF:

Polyvinylidene difluoride

SP:

Signal peptide

TRAIL:

Tumor necrosis factor related apoptosis inducing ligand

aa:

Amino acid

COX IV:

Cytochrome oxidase subunit IV

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Acknowledgements

We wish to thank Han-Fei Ding for the Bcl-2 and Bax expression plasmids. The authors have no commercial affiliations or conflicts of interest to declare. Supported by grants 9R01 AI068133-07 from the NIH, American Heart Association Ohio Valley Grant 0655387B, and a University of Toledo deArce Fellowship (to D.W.L.).

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  1. Department of Biological Sciences, The University of Toledo, Toledo, OH, 43606, USA

    Shaun Rosebeck & Douglas W. Leaman

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Correspondence to Douglas W. Leaman.

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Rosebeck, S., Leaman, D.W. Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a. Apoptosis 13, 562–572 (2008). https://doi.org/10.1007/s10495-008-0190-0

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