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J. Biol. Chem., Vol. 281, Issue 12, 8126-8134, March 24, 2006

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Gemin8 Is a Novel Component of the Survival Motor Neuron Complex and Functions in Small Nuclear Ribonucleoprotein Assembly^*

Claudia Carissimi, Luciano Saieva, Jennifer Baccon, Pieranna Chiarella^¶, Alessio Maiolica^||, Alan Sawyer^¶, Juri Rappsilber^||, and Livio Pellizzoni, EMBO Young Investigator and an Assistant Telethon Scientist¹

From the Dulbecco Telethon Institute, Institute of Cell Biology, Consiglio Nazionale delle Ricerche, 00016 Monterotondo Scalo, Rome, Italy, the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ^¶EMBL Monoclonal Antibody Core Facility, 00016 Monterotondo Scalo, Rome, Italy, and ^||The FIRC Institute for Molecular Oncology Foundation, 20139 Milan, Italy

The survival motor neuron (SMN) protein is the product of the spinal muscular atrophy disease gene. SMN and Gemin2–7 proteins form a large macromolecular complex that localizes in the cytoplasm as well as in the nucleoplasm and in nuclear Gems. The SMN complex interacts with several additional proteins and likely functions in multiple cellular pathways. In the cytoplasm, a subset of SMN complexes containing unrip and Sm proteins mediates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Here, by mass spectrometry analysis of SMN complexes purified from HeLa cells, we identified a novel protein that is evolutionarily conserved in metazoans, and we named it Gemin8. Co-immunoprecipitation and immunolocalization experiments demonstrated that Gemin8 is associated with the SMN complex and is localized in the cytoplasm and in the nucleus, where it is highly concentrated in Gems. Gemin8 interacts directly with the Gemin6-Gemin7 heterodimer and, together with unrip, these proteins form a heteromeric subunit of the SMN complex. Gemin8 is also associated with Sm proteins, and Gemin8-containing SMN complexes are competent to carry out snRNP assembly. Importantly, RNA interference experiments indicate that Gemin8 knock-down impairs snRNP assembly, and Gemin8 expression is down-regulated in cells with low levels of SMN. These results demonstrate that Gemin8 is a novel integral component of the SMN complex and extend the repertoire of cellular proteins involved in the pathway of snRNP biogenesis.

Received for publication, November 14, 2005 , and in revised form, December 21, 2005.

^* This work was supported by Telethon-Italy Grant TCP 02011, "Compagnia di San Paolo," and by a grant from the Muscular Dystrophy Association-USA. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dulbecco Telethon Institute, Institute of Cell Biology (Consiglio Nazionale delle Ricerche), Via E. Ramarini 32, Monterotondo Scalo, Rome, Italy 00016. Tel.: 39-06-90091326; Fax: 39-06-90091259; E-mail: livio.pellizzoni{at}ibc.cnr.it.

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