COMMD1 promotes the ubiquitination of NF‐κB subunits through a cullin‐containing ubiquitin ligase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102213/1/emboj7601489.pd

Targeting HIV Prevention Based on Molecular Epidemiology Among Deeply Sampled Subnetworks of Men Who Have Sex With Men.

BackgroundMolecular epidemiology can be useful in identifying clusters of human immunodeficiency virus (HIV) transmission that can be targeted for prevention.MethodsRegular screening of 2000 men who have sex with men (MSM) in Beijing, China, for HIV infection every 2 months identified 179 primary infections (2007-2010). HIV-1 pol sequences were obtained and used to infer the transmission network and identify transmitted drug resistance (TDR) among these individuals. We evaluated the use of clinical and network information to target prevention efforts. Prevention efficiency was calculated as the number of infections saved per number of interventions.ResultsThis cohort was infected with HIV-1 subtype B (28%), circulating recombinant form (CRF)_01 AE (53%), and CRF_07 BC (16%). The overall rate of TDR was low (5%), but the rate of clustering was high (64%), suggesting deep sampling of the subnetwork. Provision of a theoretically high-efficacy intervention like antiretroviral therapy to all participants had a prevention efficiency of 23%. The efficiency of targeting prevention based on lower CD4 counts (<200 cells/mL, <350 cells/mL, or <500 cells/mL) and higher viral loads (>100 000 copies/mL and >50 000 copies/mL) was between 10% and 18%. The efficiency of targeting prevention based on number of network connections was much higher (30%-42%). For example, treating the 33 participants with ≥5 connections in 2009 would have theoretically prevented 14 infections in 2010 (42% prevention efficiency).ConclusionsRegular HIV testing of MSM in Beijing can deeply sample the local transmission subnetwork, and targeting prevention efforts based on network connectivity may be an efficient way to deliver prevention interventions

CCDC22 deficiency in humans blunts activation of proinflammatory NF-kappa B signaling

NF-kappa B is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory I kappa B proteins. In addition, the inactivation of DNA-bound NF-kappa B is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-kappa B blockade. Indeed, patient-derived cells demonstrated impaired NF-kappa B activation due to decreased I kappa B ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of I kappa B proteins. Taken together, our results indicate that CCDC22 participates in NF-kappa B activation and that its deficiency leads to decreased I kappa B turnover in humans, highlighting an important regulatory component of this pathway