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J. Biol. Chem., Vol. 280, Issue 14, 13801-13808, April 8, 2005

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Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor^*

Michelle S. Linggi, Tara L. Burke, B. Blairanne Williams, Anthony Harrington, Rosemary Kraemer¶||, Barbara L. Hempstead**, Sung Ok Yoon, and Bruce D. Carter

From the Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, the Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, and the Departments of ^**Medicine, ^¶Pathology, and ^||Cell Biology, Weill Medical College of Cornell University, New York, New York 10021

Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif–/– sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif–/– neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.

Received for publication, September 10, 2004 , and in revised form, December 14, 2004.

^* This work was supported by Grants NS38220 (to B. D. C.), T32 HL07328 (to M. S. L.), NS39472 (to S. O. Y.), and NS30687 (to B. L. H.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biochemistry, 655 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-936-3041; Fax: 615-343-0704; E-mail: bruce.carter{at}vanderbilt.edu.

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