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N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1 -/-IEC and AnxA1 -/-mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.

Symbionts often exhibit significant reductions in genome complexity while pathogens often exhibit increased complexity through acquisition and diversification of virulence determinants. A few organisms have evolved complex life cycles in which they interact as symbionts with one host and pathogens with another. How the predicted and opposing influences of symbiosis and pathogenesis affect genome evolution in such instances, however, is unclear. The Polydnaviridae is a family of double-stranded (ds) DNA viruses associated with parasitoid wasps that parasitize other insects. Polydnaviruses (PDVs) only replicate in wasps but infect and cause severe disease in parasitized hosts. This disease is essential for survival of the parasitoid's offspring. Thus, a true mutualism exists between PDVs and wasps as viral transmission depends on parasitoid survival and parasitoid survival depends on viral infection of the wasp's host. To investigate how life cycle and ancestry affect PDVs, we compared the genomes of Campoletis sonorensis ichnovirus (CsIV) and Microplitis demolitor bracovirus (MdBV). CsIV and MdBV have no direct common ancestor, yet their encapsidated genomes share several features including segmentation, diversification of virulence genes into families, and the absence of genes required for replication. In contrast, CsIV and MdBV share few genes expressed in parasitized hosts. We conclude that the similar organizational features of PDV genomes reflect their shared life cycle but that PDVs associated with ichneumonid and braconid wasps have likely evolved different strategies to cause disease in the wasp's host and promote parasitoid survival.

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Small ubiquitin-like modifier (SUMO) 1 is a protein of 97 amino acids that is structurally similar to ubiquitin and has been called by other names including Smt3p, Pmt2p, PIC-1, GMP1, Ubl1, and Sentrin (1). Like ubiquitin, SUMO has been found to be covalently attached to certain lysine residues of specific target proteins (2). In contrast to ubiquitination, however, sumoylation does not promote the degradation of proteins but instead alters a number of different functional parameters of proteins, depending on the protein substrate in question. These parameters include but are not limited to properties such as subcellular localization, protein partnering, and DNA-binding and/or transactivation functions of transcription factors (2-4). The contrast between the functional effects of ubiquitination and sumoylation is most striking in the case of IB, where sumoylation stabilizes the protein by modifying the same residue that is ubiquitinated, thereby directly competing with that pathway (5). This review will focus on the regulation of SUMO modification and its role in controlling the functional properties of proteins. The reader is also referred to other excellent reviews on this topic (2-4, 6 -8). Enzymology and Regulation of SUMO Conjugationand Deconjugation Three different ubiquitous SUMO-related proteins have been identified in mammalian cells, SUMO-1, SUMO-2, and SUMO-3, with SUMO-2 and SUMO-3 having greater sequence relatedness with each other than with 4). Recently a tissue-specific SUMO-4 has been identified in human kidney with homology to SUMO-2/3, which raises the possibility that some SUMO proteins could have tissue-dependent functions (9). SUMO modification occurs on the lysine in the consensus sequence ⌿KXE (where ⌿ represents a hydrophobic amino acid, and X represents any amino acid) (2, 3). The mechanism involved in maturation and transfer of SUMO to target substrates is very similar to that seen with ubiquitination and other ubiquitin-like proteins (3, 4). This process involves four enzymatic steps: maturation, activation, conjugation, and ligation ( Fig. 1). In the first step the SUMO protein is cleaved by SUMO-specific carboxyl-terminal hydrolase to produce a carboxyl-terminal diglycine motif. This process of maturation is identical with all three mammalian SUMO forms. After maturation, SUMO proteins are able to be utilized for conjugation to proteins. The SUMO-activating (E1) enzyme is a heterodimer consisting of Aos1 and Uba2 (also known as SAE1/SAE2 or Sua1/hUba2 in humans). Activation of SUMO by the E1 is an ATP-dependent process and results in the formation of a thioester bond between SUMO and the Uba2 subunit of the E1-activating enzyme. Activation is followed by transfer of SUMO from the E1 enzyme to a conserved cysteine in the conjugating (E2) enzyme, Ubc9. This single E2 enzyme identified so far for the sumoylation pathway contrasts with the multiple E2 enzymes involved in attaching ubiquitin to proteins (4, 10).The final step of sumoylation involves ligation of SUMO to the target protei...