Emerging roles of immunoproteasomes beyond MHC class I antigen processing

The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8(+) T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression.     

Maize HapMap2 identifies extant variation from a genome in flux

Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize.     

CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality. Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1:15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending. Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci. Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Apolipoprotein M affecting lipid metabolism or just catching a ride with lipoproteins in the circulation?

Apolipoprotein M (apoM) is a novel apolipoprotein found mainly in high-density lipoproteins (HDL). Its function is yet to be defined. ApoM (25 kDa) has a typical lipocalin ?-barrel fold and a hydrophobic pocket. Retinoids bind apoM but with low affinity and may not be the natural ligands. ApoM retains its signal peptide, which serves as a hydrophobic anchor to the lipoproteins. This prevents apoM from being lost in the urine. Approximately 5% of HDL carries an apoM molecule. ApoM in plasma (1 μM) correlates strongly with both low-density lipoprotein (LDL) and HDL cholesterol, suggesting a link to cholesterol metabolism. However, in casecontrol studies, apoM levels in patients with coronary heart disease (CHD) and controls were similar, suggesting apoM levels not to affect the risk for CHD in humans. Experiments in transgenic mice suggested apoM to have antiatherogenic properties; possible mechanisms include increased formation of pre-? HDL, enhanced cholesterol mobilization from foam cells, and increased antioxidant properties. Received 28 November 2008; received after revision 15 December 2008; accepted 16 December 2008     

miR-1, miR-10b,miR-155, and miR-191 are novel regulators of BDNF

Brain-derived neurotrophic factor (BDNF) is a secreted protein of the neurotrophin family that regulates brain development, synaptogenesis, memory and learning, as well as development of peripheral organs, such as angiogenesis in the heart and postnatal growth and repair of skeletal muscle. However, while precise regulation of BDNF levels is an important determinant in defining the biological outcome, the role of microRNAs (miRs) in modulating BDNF expression has not been extensively analyzed. Using in silico approaches, reporter systems, and analysis of endogenous BDNF, we show that miR-1, miR-10b, miR-155, and miR-191 directly repress BDNF through binding to their predicted sites in BDNF 3′UTR. We find that the overexpression of miR-1 and miR-10b suppresses endogenous BDNF protein levels and that silencing endogenous miR-10b increases BDNF mRNA and protein levels. Furthermore, we show that miR-1/206 binding sites within BDNF 3′UTR are used in differentiated myotubes but not in undifferentiated myoblasts. Finally, our data from two cell lines suggest that endogenous miR-1/206 and miR-10 family miRs act cooperatively in suppressing BDNF through their predicted sites in BDNF 3′UTR. In conclusion, our results highlight miR-1, miR-10b, miR-155, and miR-191 as novel regulators of BDNF long and short 3′UTR isoforms, supporting future research in different physiological and pathological contexts.     

A common variant associated with prostate cancer in European and African populations

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.