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* Center for Computational and Integrative Biology,
Gastrointestinal Unit, Center for Inflammatory Bowel Disease, and
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;
¶ Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan;
|| The Broad Institute of Massachussetts Institute of Technology and Harvard, Cambridge, MA 02142; and
# University of Texas Southwestern Medical Center, Dallas, TX 75390
Autophagy is a conserved cellular process required for the removal of defective organelles, protein aggregates, and intracellular pathogens. We used a network analysis strategy to identify novel human autophagy components based upon the yeast interactome centered on the core yeast autophagy proteins. This revealed the potential involvement of 14 novel mammalian genes in autophagy, several of which have known or predicted roles in membrane organization or dynamics. We selected one of these membrane interactors, FNBP1L (formin binding protein 1-like), an F-BAR-containing protein (also termed Toca-1), for further study based upon a predicted interaction with ATG3. We confirmed the FNBP1L/ATG3 interaction biochemically and mapped the FNBP1L domains responsible. Using a functional RNA interference approach, we determined that FNBP1L is essential for autophagy of the intracellular pathogen Salmonella enterica serovar Typhimurium and show that the autophagy process serves to restrict the growth of intracellular bacteria. However, FNBP1L appears dispensable for other forms of autophagy induced by serum starvation or rapamycin. We present a model where FNBP1L is essential for autophagy of intracellular pathogens and identify FNBP1L as a differentially used molecule in specific autophagic contexts. By using network biology to derive functional biological information, we demonstrate the utility of integrated genomics to novel molecule discovery in autophagy.
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.
1 This work was supported National Institutes of Health Grants AI062773, DK83756, and DK043351 (to R.J.X., M.J.D., and A.H.) and DK060049 and DK043351 (to D.K.P.). A.N. is supported by a Crohn’s and Colitis Foundation of America fellowship.
2 A.H. and A.N. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ramnik J. Xavier, Center for Computational and Integrative Biology, Massachusetts General Hospital, Richard B. Simches Research Center, 185 Cambridge Street, 7th Floor, Boston, MA 02114. E-mail address: Xavier{at}molbio.mgh.harvard.edu
4 Abbreviations used in this paper: siRNA, small interfering RNA; AFA, ancillary factors of autophagy; MEF, mouse embryonic fibroblast; MOI, multiplicity of infection; RNAi, RNA interference; SCV, Salmonella-containing vacuole; S. Typhimurium, Salmonella enterica serovar Typhimurium.
5 The online version of this article contains supplemental material.
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  T. Noda and T. Yoshimori Molecular basis of canonical and bactericidal autophagy Int. Immunol., November 1, 2009; 21(11): 1199 - 1204. [Abstract] [Full Text] [PDF]
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