It was demonstrated that modulation of the proteasome activity is effective in attenuating experimental colitis. The results reveal that reduction of the proteasome activity either by partial inhibition with bortezomib or by specifically targeting the immunoproteasome subunit LMP7 is a suitable treatment of intestinal inflammation.

The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance.

Chlamydia, a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with its capacity to cause extensive host DNA damage, this poses a potential risk of malignant transformation, consistent with circumstantial epidemiological evidence. Here we reveal a dramatic depletion of p53, a tumor suppressor deregulated in many cancers, during Chlamydia infection. Using biochemical approaches and live imaging of individual cells, we demonstrate that p53 diminution requires phosphorylation of Murine Double Minute 2 (MDM2; a ubiquitin ligase) and subsequent interaction of phospho-MDM2 with p53 before induced proteasomal degradation. Strikingly, inhibition of the p53–MDM2 interaction is sufficient to disrupt intracellular development of Chlamydia and interferes with the pathogen’s anti-apoptotic effect on host cells. This highlights the dependency of the pathogen on a functional MDM2-p53 axis and lends support to a potentially pro-carcinogenic effect of chlamydial infection.

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In those proteins, an essential metal ion is bound by a metal ion-dependent adhesion site (MIDAS). The MIDAS is presented at the apex of a larger protein module called an I domain. The metal ligands in the MIDAS can be separated into three distantly spaced clusters of oxygenated residues. These three coordination sites also appear to exist in the integrin ␤3 and ␤5 subunits. Here, we examined the putative metal binding site within ␤3 and ␤5 using site-directed mutagenesis and ligand binding studies. We also investigated the fold of the domain containing the putative metal binding site using the PHD structural algorithm. The results of the study point to the similarity between the integrin ␤ subunits and the MIDAS motif at two of three key coordination points. Importantly though, the study failed to identify a residue in either ␤ subunit that corresponds to the second metal coordination group in the MIDAS. Moreover, structural algorithms indicate that the fold of the ␤ subunits is considerably different than the I domains. Thus, the integrin ␤ subunits appear to present a MIDAS-like motif in the context of a protein module that is structurally distinct from known I domains.Integrins are ␣␤ heterodimers that mediate cell adhesion (1, 2). Integrins participate in development and tissue remodeling and are linked to several diseases. The integrins bind to many adhesive and extracellular matrix proteins. The focal points of this study are the ␣v␤3 and ␣v␤5 integrins, both of which recognize the Arg-Gly-Asp (RGD) 1 tripeptide motif. The ␣v␤3 integrin binds to at least nine adhesive proteins and has two important biological functions. First, ␣v␤3 mediates the adhesion of osteoclasts to the bone surface (3), an event often considered to be the first step in bone resorption (4). Second, the ␣v␤3 integrin is expressed on the surface of angiogenic endothelial cells, where it is required for cell survival and further vessel development (5-7). It has been suggested that inhibitors of the ␣v␤3 integrin could be applied as antagonists of osteoporosis and tumor angiogenesis. The biological function of the ␣v␤5 integrin is less clear. This integrin can mediate cell adhesion to vitronectin. The ␣v␤5 integrin is also required for the internalization of adenovirus (8, 9), and it may be associated with angiogenesis (7).All integrins require divalent cations to bind their ligands. An important clue to the structural basis for ion binding was revealed by the crystal structures of the I domains from the integrin ␣ L and ␣ M subunits (10, 11). Each I domain spans approximately 200 residues and is homologous to an "inserted" domain in a number of other proteins including von Willebrand factor (12). In ␣ L and ␣ M , the I domain is necessary and sufficient for ligand contact. These I domains contain a metal binding site called a MIDAS (metal ion-dependent adhesion site). This ion binding site consists of five liganding residues that can be separated into three groups. Each group of coordinating residues is located at separate positions wit...