MURR1 is a multifunctional protein that inhibits nuclear factor B (NF-B), a transcription factor with pleiotropic functions affecting innate and adaptive immunity, apoptosis, cell cycle regulation, and oncogenesis. Here we report the discovery of a new family of proteins with homology to MURR1. These proteins form multimeric complexes and were identified in a biochemical screen for MURR1-associated factors. The family is defined by the presence of a conserved and unique motif termed the COMM (copper metabolism gene MURR1) domain, which functions as an interface for proteinprotein interactions. Like MURR1, several of these factors also associate with and inhibit NF-B. The proteins designated as COMMD or COMM domain containing 1-10 are extensively conserved in multicellular eukaryotic organisms and define a novel family of structural and functional homologs of MURR1. The prototype of this family, MURR1/COMMD1, suppresses NF-B not by affecting nuclear translocation or binding of NF-B to cognate motifs; rather, it functions in the nucleus by affecting the association of NF-B with chromatin.NF-B is a dimeric complex formed by members of a highly conserved family of proteins that share a defining motif designated the Rel homology domain (RHD).1 Through transcriptional regulation of many gene products, NF-B participates in a number of biological processes including innate and adaptive immune responses, programmed cell death, cell cycle progression, and oncogenesis (1-6). Additionally, by its ability to regulate transcription of various viral genomes including human immunodeficiency virus-1 (HIV-1) (7-10), NF-B also participates in viral cycle progression.Studies into the regulation of NF-B activation have largely focused on the role of cytoplasmic sequestration of the NF-B complex as a mainstay level of control. In most cells NF-B is localized in the cytoplasm through the interaction of the complex with members of the IB family (11). These proteins contain ankyrin repeats that allow their interaction with NF-B and mask the nuclear localization signal present in the RHD. Phosphorylation of IB by a multimeric kinase known as the IB kinase complex targets these proteins for ubiquitination and proteasomal degradation (3,12). This allows the translocation of NF-B to the nucleus where it binds to cognate DNA sequences present in an array of gene promoters.MURR1 is a recently identified factor that has been shown to participate in two apparently distinct activities, regulation of the transcription factor NF-B and control of copper metabolism (13). Mutations in MURR1 are responsible for copper toxicosis in an inbred canine strain (Bedlington terriers) (14), and an interaction between MURR1 and the copper transporter ATP7B (15) has been recently reported.In addition to its role in copper metabolism in mammals, more recent studies implicate MURR1 in the regulation of the transcription factor NF-B (13, 16). MURR1 was found to be a broad inhibitor of NF-B, affecting B-responsive transcription from endogenous and viral promoters in...

Using a mouse model of multiple sclerosis (MS), the authors show that neutrophils expand in the bone marrow and accumulate in the circulation before clinical onset of disease. Early in disease development, neutrophils infiltrate the CNS, which is suppressed by G-CSF receptor deficiency and blockade of CXCL1 to ameliorate disease. In patients with MS, systemic expression of neutrophil-related mediators correlates with new lesion formation, lesion burden, and clinical disability.

waf1 . Furthermore, p21 waf1 expression and cell cycle arrest were found to depend predominantly on the canonical NF-B pathway, since it was reversed by RNA interference-mediated suppression of RelA. In contrast, suppression of the p100/p52 NF-B subunit had little effect on p21 waf1 . These data reveal that in ALCL cells, in contrast to other cell types, CD30 stimulation elicits p21 waf1 -mediated arrest through the canonical but not the alternative NF-B pathway.

Cases of progressive multifocal leukoencephalopathy can occur in patients treated with the B cell depleting anti-CD20 antibody, rituximab, highlighting the importance of B cell surveillance of the central nervous system (CNS). The lymphoid chemokine, CXCL13, is critical for B cell recruitment and functional organization of peripheral lymphoid tissues, and CXCL13 levels are often elevated in the inflamed CNS. To more directly investigate the role of CXCL13 in CNS B cell migration, its role in animal models of infectious and inflammatory demyelinating disease was examined. During acute alphavirus encephalitis where viral clearance depends on the local actions of anti-viral antibodies, CXCL13 levels and B cell numbers increased in brain tissue over time. Surprisingly, however, CXCL13-deficient animals showed normal CNS B cell recruitment, unaltered CNS virus replication and clearance, and intact peripheral anti-viral antibody responses. During experimental autoimmune encephalomyelitis (EAE), CNS levels of CXCL13 increased as symptoms emerged and equivalent numbers of B cells were identified among the CNS infiltrates of CXCL13-deficient mice compared to control animals. However, CXCL13-deficient mice did not sustain pathogenic anti-myelin T cell responses, consistent with their known propensity to develop more self-limited EAE. These data show that CXCL13 is dispensable for CNS B cell recruitment in both models. The disease course is unaffected by CXCL13 in a CNS infection paradigm that depends on a pathogen-specific B cell response, while it is heightened and prolonged by CXCL13 when myelin-specific CD4+ T cells drive CNS pathology. Thus, CXCL13 could be a therapeutic target in certain neuroinflammatory diseases, but not by blocking B cell recruitment to the CNS.

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