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The Bush Administration steps up its secret moves against Iran". The Wall Street Journal. Scratching the Surface of a Known Unknown", a redacted version of Smith's report is available online via the blog site owned by American military geostrategist and The Pentagon's New Map author Thomas P. Articles containing Persian-language text Wikipedia articles incorporating text from the United States Army Wikipedia articles incorporating text from public domain works of the United States Government Webarchive template wayback links All articles with dead external links Articles with dead external links from May CS1 maint:


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However, Iran claims it is merely "ensuring the survival of the regime" by propagating regional influence. See also Figure S1. Retrieved 16 October Armed forces of Iran. Both during and after the war, it provided support to the Kurds fighting Saddam Hussein.

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In this study we have shown that human IRGM, hitherto believed to have indirect effects on autophagy, directly governs the assembly of the principal autophagy regulators. However, the role of Klinked polyubiquitination has also begun to be appreciated as a mechanism for stabilization of large autophagy-initiating complexes Nazio et al. In contrast to the above suite of autophagy regulators, Beclin 1 was not affected Figure S2C. In keeping with its autophagy-mediated antimicrobial role, IRGM is additionally a genetic risk factor for tuberculosis in different human populations Intemann et al. Its orthologs are present only in African great apes and Homo sapiens but active alleles are absent in ancestral evolutionary lineages leading up to them Bekpen et al. Ubiquitination has been implicated in autophagy in several ways primarily in targeting of substrates for autophagic elimination Stolz et al. See also Figure S5. Based on the above experiments with IRGM-K mut , the properties of IRGM that are essential for the assembly of the core autophagy machinery affect its antimicrobial and inflammatory outputs. Using a model system of transfected epithelial cells previously developed by others Brest et al. Although the overall magnitude of the effects on bacterial killing was subtle, it was in keeping with the known limitations of the system Brest et al. The prevailing view of the murine IRGs is that they have predominantly non-autophagy functions Choi et al. J Schematic summary of the results obtained in Figure 3E—I. Results representative of three independent experiments. This point is not trivial, as for example it has not been easy to connect the two seemingly separate systems of autophagy initiation: LC3-II conjugation and localized autophagosomal membrane build up. However, when a monocytic cell line THP-1 was infected with E. For induction of autophagy by starvation, cells were cultured in EBSS. Thus, exposure of cells to microbes or their products affects IRGM expression and also influences interactions with the autophagic apparatus Figure 3J. Author information Copyright and License information Disclaimer. Polyubiquitination of IRGM and its role in autophagy Figure 7J does not play a role in targeting substrates for autophagy; instead, it stabilizes multi-protein autophagy initiation complexes. Supplementary information includes Extended Experimental Procedures and seven figures. National Center for Biotechnology Information , U.

IRGM, encoded by a uniquely human gene conferring risk for inflammatory diseases, affects autophagy through a hitherto unknown mechanism. Thomas Kufer University of Cologne, Germany. We interpret this dichotomy as a part of the well tuned circuitry in response to microbial challenge: MDP tolerance is an important mechanism to avoid septic shock, which is in part achieved by NOD2 degradation Zurek et al.

The publisher's final edited version of this article is available at Mol Cell. IRGM gene expression is cell-type dependent and responds to both starvation and microbial products. M Beclin 1 domain organization indicating its interacting proteins along with deletion constructs used in Co-IP analysis in panel L. Thus, IRGM controls several points along the autophagy pathway and contributes to efficient xenophagy.

See also Figure S3. Autophagy is a cellular homeostatic mechanism with broad roles in human health and disease Mizushima et al. Bottom, fluorescence intensity line tracing corresponding to dashed line. Numbers beneath bands in B, C, quantification of phosphorylated proteins relative to the total abundance of the same protein.

Bottom, fluorescence intensity line tracing corresponding to red line. IRGM is particularly inducible in cells intestinal epithelial cells and macrophages derived from tissues affected in diseases where IRGM has been implicated as a genetic risk factor: CD and tuberculosis Consortium, ; Craddock et al.

Blot in E was processed to remove irrelevant lanes dashed vertical line. Together, these molecular events promote antimicrobial autophagy and suppress excessive inflammatory responses. Consistent with this observation, a monocytic cell line THP-1 infected with E. For co-immunoprecipitation assays, the cells were lysed using NP buffer containing protease inhibitor cocktail and PMSF.

Prior work has indicated that IRGM affects autophagy through processes influencing mitochondrial function, including mitochondrial fission and membrane potential collapse Singh et al. Thus, the system responds to a range of inputs such as starvation Mizushima et al. Blot was processed dashed vertical line to remove irrelevant lanes.

The apparent absence of effects on Beclin 1 stability may be explained by the bulk of Beclin 1 being predominantly in non-autophagy related hVPS34 complexes whereas ATG14L-associated Beclin 1 represents a minority of Beclin 1 species in the cell Kim et al. This explains the hitherto mysterious role of IRGM in autophagy, places it at the center of molecular complexes controlling and executing autophagy, and molecularly connects biological inputs with autophagic outputs.

The entire signaling cascade described above could explain how IRGM induces autophagy, e. Flag-NOD2 and variants were from Dr. Protein interactions analyses For co-immunoprecipitation assays, the cells were lysed using NP buffer containing protease inhibitor cocktail and PMSF.

Supplementary Material Click here to view. Thus, IRGM plays a direct role in organizing the core autophagy machinery to endow it with antimicrobial and anti-inflammatory functions. This is a PDF file of an unedited manuscript that has been accepted for publication. In conclusion, IRGM orchestrates antimicrobial autophagic responses. Not only does IRGM amplify this fundamental autophagy signaling but it also assembles the core autophagy machinery.

IRGM controls not just initiation of autophagy but may also affect its maturation. Thus, IRGM promotes phosphorylation cascade of key autophagy regulators and assembles them into autophagy initiation complexes Figure 7J. Thus, we tested the activation status of AMPK. Moreover, IRGM affects the stability of each of the components of this complex.

Thus, IRGM and possibly its distant IRG homologs in other vertebrates may act as transmission modules between a selective sub-repertoire of innate immune responses and the autophagy machinery. Bottom, fluorescence intensity line tracing. See other articles in PMC that cite the published article. Autophagy is at the intersection of metabolic Mizushima et al.

Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Thus the significant information gathered in the murine systems may have limited import on how the human IRGM works. C Effect of E. IRGM has been shown to control intracellular bacteria Brest et al.

As a service to our customers we are providing this early version of the manuscript. Lysates were incubated with antibody for 2 h followed by incubation with proteinG Dynabeads Life technologies for 2 h. Author manuscript; available in PMC May 7. IRGM has no homologs among the Atg genes in yeast, which makes it difficult to assign to it an autophagy-specific function; instead, IRGM has been considered to affect autophagy indirectly Singh et al.

Immunoblots were quantified using Image J software. Autophagic responses to PAMPS lead to direct antimicrobial action through a process termed xenophagy and control of inflammation and other immune processes Deretic et al. This solves the long-standing puzzle regarding how IRGM works, and places it mechanistically at the center of action in autophagic responses to microbes.

See also Figure S1. The induction of IRGM was similar to other physiological inducers of autophagy: Thus, IRGM is required for autophagy elicited by microbial products. Details as for panel E. See also Figure S6. In summary, in addition to directing the assembly of key autophagy-specific regulators, IRGM also stabilizes them.

NOD2 is known to promote ubiquitination of several target proteins Abbott et al. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Acknowledgments We thank R.

IRGM interacted with two Beclin 1 regions: The above data indicate that IRGM forms protein complexes with the central regulators of autophagy and activates Beclin 1 by displacing its negative regulators Figure 1O , Right. Here we show how IRGM controls autophagy. However, IRGM showed a further, more direct role by interacting with the key regulators of autophagy. We acknowledge contributions by D. A complicating factor in understanding the exact function of IRGM is that it is distinctly a human gene Bekpen et al. Furthermore, it physically links the microbial sensors, including NOD2, to the core autophagic apparatus. To determine which ubiquitination linkage was involved, we co-expressed GFP-IRGM with two HA-tagged ubiquitin variants, one that can be ubiquitinated only at K63 and another one that can be ubiquitinated only at K A similar phenomenon, i. IRGM affects antimicrobial and inflammatory outputs and interfaces with several innate immunity systems IRGM has been shown to control intracellular bacteria Brest et al. Associated Data Supplementary Materials. Right, densitometric analysis of Western blots using ImageJ software. See also Figure S4. See also Figure S2. Open in a separate window. Results, representative of three independent experiments. See also Figure S7.
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