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Vol. 14, Issue 8, 3292-3304, August 2003

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Irod/Ian5: An Inhibitor of -Radiation- and Okadaic Acid-induced Apoptosis

Tone Sandal ^*, Linda Aumo ^*, Lars Hedin ^*, Bjørn T. Gjertsen , and Stein O. Døskeland ^* 

^* Department of Anatomy and Cell Biology, Medical faculty, University of Bergen, N-5009 Bergen, Norway; Selection of Molecular Hematology, Department of Internal Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

Submitted October 31, 2002; Revised February 3, 2003; Accepted February 19, 2003
Monitoring Editor: Carl-Henrik Heldin

Protein phosphatase-directed toxins such as okadaic acid (OA) are general apoptosis inducers. We show that a protein (inhibitor of radiation- and OA-induced apoptosis, Irod/Ian5), belonging to the family of immune-associated nucleotide binding proteins, protected Jurkat T-cells against OA- and -radiation-induced apoptosis. Unlike previously described antiapoptotic proteins Irod/Ian5 did not protect against anti-Fas, tumor necrosis factor-, staurosporine, UV-light, or a number of chemotherapeutic drugs. Irod antagonized a calmodulin-dependent protein kinase II-dependent step upstream of activation of caspase 3. Irod has predicted GTP-binding, coiled-coil, and membrane binding domains. Irod localized to the centrosomal/Golgi/endoplasmic reticulum compartment. Deletion of either the C-terminal membrane binding domain or the N-terminal GTP-binding domain did not affect the antiapoptotic function of Irod, nor the centrosomal localization. The middle part of Irod, containing the coiled-coil domain, was therefore responsible for centrosomal anchoring and resistance toward death. Being widely expressed and able to protect also nonimmune cells, the function of Irod may not be limited to the immune system. The function and localization of Irod indicate that the centrosome and calmodulin-dependent protein kinase II may have important roles in apoptosis signaling.

Abbreviations used: As-Irod, antisense-Irod; CaMKII, Ca²⁺/calmodulin-dependent kinase II, ER, endoplasmic reticulum; GFP, green fluorescence protein; HA, hemagglutinin; HDM2, human MDM2; Irod, inhibitor of radiation- and okadaic acid-induced death; OA, okadaic acid; PP, protein phosphatase.

Corresponding author. E-mail address: stein.doskeland{at}iac.uib.no.

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