Sun Shim Choi

Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity.

Postcopulatory sperm competition is a key aspect of sexual selection and is believed to drive the rapid evolution of both reproductive physiology and reproduction-related genes. It is well-established that mating behavior determines the intensity of sperm competition, with polyandry (i.e., female promiscuity) leading to fiercer sperm competition than monandry. Studies in mammals, particularly primates, showed that, owing to greater sperm competition, polyandrous taxa generally have physiological traits that make them better adapted for fertilization than monandrous species, including bigger testes, larger seminal vesicles, higher sperm counts, richer mitochondrial loading in sperm and more prominent semen coagulation. Here, we show that the degree of polyandry can also impact the dynamics of molecular evolution. Specifically, we show that the evolution of SEMG2, the gene encoding semenogelin II, a main structural component of semen coagulum, is accelerated in polyandrous primates relative to monandrous primates. Our study showcases the intimate relationship between sexual selection and the molecular evolution of reproductive genes.

Transglutaminase 2: a multi-functional protein in multiple subcellular compartments.

Transglutaminase 2 (TG2) is a multifunctional protein that can function as a transglutaminase, G protein, kinase, protein disulfide isomerase, and as an adaptor protein. These multiple biochemical activities of TG2 account for, at least in part, its involvement in a wide variety of cellular processes encompassing differentiation, cell death, inflammation, cell migration, and wound healing. The individual biochemical activities of TG2 are regulated by several cellular factors, including calcium, nucleotides, and redox potential, which vary depending on its subcellular location. Thus, the microenvironments of the subcellular compartments to which TG2 localizes, such as the cytosol, plasma membrane, nucleus, mitochondria, or extracellular space, are important determinants to switch on or off various TG2 biochemical activities. Furthermore, TG2 interacts with a distinct subset of proteins and/or substrates depending on its subcellular location. In this review, the biological functions and molecular interactions of TG2 will be discussed in the context of the unique environments of the subcellular compartments to which TG2 localizes.

Expression breadth and expression abundance behave differently in correlations with evolutionary rates

BackgroundOne of the main objectives of the molecular evolution and evolutionary systems biology field is to reveal the underlying principles that dictate protein evolutionary rates. Several studies argue that expression abundance is the most critical component in determining the rate of evolution, especially in unicellular organisms. However, the expression breadth also needs to be considered for multicellular organisms.ResultsIn the present paper, we analyzed the relationship between the two expression variables and rates using two different genome-scale expression datasets, microarrays and ESTs. A significant positive correlation between the expression abundance (EA) and expression breadth (EB) was revealed by Kendalls rank correlation tests. A novel random shuffling approach was applied for EA and EB to compare the correlation coefficients obtained from real data sets to those estimated based on random chance. A novel method called a Fixed Group Analysis (FGA) was designed and applied to investigate the correlations between expression variables and rates when one of the two expression variables was evenly fixed.ConclusionsIn conclusion, all of these analyses and tests consistently showed that the breadth rather than the abundance of gene expression is tightly linked with the evolutionary rate in multicellular organisms.

Robust signals of coevolution of interacting residues in mammalian proteomes identified by phylogeny-aided structural analysis

The structure of a protein depends critically on the complex interactions among its amino acid residues. It has long been hypothesized that interacting residues might tend to coevolve, but it is not known whether such coevolution is a general phenomenon across the proteome. Here, we describe a novel methodology called phylogeny-aided structural analysis, which uncovers robust signals of interacting-residue coevolution in mammalian proteomes. Furthermore, this new method allows the magnitude of coevolution to be quantified. Finally, it facilitates a comprehensive evaluation of various factors that affect interacting-residue coevolution, such as the physicochemical properties of the interactions between residues, solvent accessibility of the residues and their secondary structure context.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-β Production

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-β in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

SMG5–PNRC2 is functionally dominant compared with SMG5–SMG7 in mammalian nonsense-mediated mRNA decay

In mammals, nonsense-mediated mRNA decay (NMD) functions in post-transcriptional gene regulation as well as mRNA surveillance. A key NMD factor, Upf1, becomes hyperphosphorylated by SMG1 kinase during the recognition of NMD substrates. Hyperphosphorylated Upf1 interacts with several factors including SMG5, SMG6, SMG7 and PNRC2 to trigger rapid mRNA degradation. However, the possible cross-talk among these factors and their selective use during NMD remain unknown. Here, we show that PNRC2 is preferentially complexed with SMG5, but not with SMG6 or SMG7, and that downregulation of PNRC2 abolishes the interaction between SMG5 and Dcp1a, a component of the decapping complex. In addition, tethering experiments reveal the function of Upf1, SMG5 and PNRC2 at the same step of NMD and the requirement of SMG6 for Upf1 for efficient mRNA degradation. Intriguingly, microarray results reveal the significant overlap of SMG5-dependent NMD substrates more with PNRC2-dependent NMD substrates than with SMG7-dependent NMD substrates, suggesting the functional dominance of SMG5-PNRC2, rather than SMG5-SMG7, under normal conditions. The results provide evidence that, to some extent, endogenous NMD substrates have their own binding preference for Upf1-interacting adaptors or effectors.

High-fat diet-induced obesity increases lymphangiogenesis and lymph node metastasis in the B16F10 melanoma allograft model: roles of adipocytes and M2-macrophages.

To examine the effects of high‐fat diet (HFD) on melanoma progression, HFD‐fed C57BL/6N mice were subcutaneously injected with syngeneic B16F10 melanoma cells. At 3 weeks post‐injection, the tumors were resected; the mice were then sacrificed at 2 weeks post‐resection. HFD stimulated melanoma growth and lymph node (LN) metastasis as well as tumor and LN lymphangiogenesis. Lipid vacuoles in the tumor and M2‐macrophage (MΦ)s in the adipose and tumor tissues were increased in HFD‐fed mice. CCL19 and CCL21 contents were higher in LNs than in tumors. HFD increased both CCL19 and CCL21 levels in LNs and CCR7 in tumors. Adipose tissue‐conditioned media (CM) from HFD‐fed mice enhanced lymphangiogenesis, and mature adipocyte (MA)/M2‐MΦ co‐culture CM markedly stimulated the tube formation of lymphatic endothelial cell (LEC)s and B16F10 migration. Monocyte migration was moderately stimulated by B16F10 or MA CM, but tremendously stimulated by B16F10/M2‐MΦ co‐culture CM, which was enhanced by MA/B16F10/M2‐MΦ co‐culture CM. The co‐culture results revealed that MAs increased CCL2, M‐CSF and CCR7 mRNAs in B16F10s; vascular endothelial growth factor (VEGF)‐D mRNA in M2‐MΦs; and CCL19, CCL21 and VEGF receptor (VEGFR)3 mRNA in LECs. M2‐MΦs increased CCL2, M‐CSF and VEGF‐A mRNAs in B16F10s, whereas B16F10s increased VEGF‐C mRNAs in M2‐MΦs and VEGFR3 mRNA in LECs. These results indicate that in HFD‐fed mice, MA‐induced CCL2 and M‐CSF in tumor cells increase M2‐MΦs in tumor; the crosstalk between tumor cells and M2‐MΦs further increases cytokines and angiogenic and lymphangiogenic factors. Additionally, MA‐stimulated CCL19, CCL21/CCR7 axis contributes to increased LN metastasis in HFD‐fed mice.

The radial glia antibody RC2 recognizes a protein encoded by Nestin

The RC2 antibody is widely used to label mouse radial glial cells in the developing central nervous system. While the antibody is known to recognize a 295-kDa intermediate filament proximal protein, the gene encoding the RC2 antigen remains to be identified. Here, we present evidences clearly demonstrating that Nestin encodes the RC2 antigen. First, the RC2 antigen and nestin have the same molecular weight and very similar tissue distribution. Second, genetic manipulations altering nestin expression also exert the same effect on the expression of the RC2 antigen. In particular, Nestin null mutation completely abolishes the RC2 immunoreactivity. Third, the expression of a truncated mouse nestin in Nestin-/- cells produces a small RC2 antigen whose size is the same to that of the truncated nestin. Furthermore, our data suggest that the RC2 antibody recognizes the C-terminal domain of nestin with unidentified posttranslational modification(s).

Interleukin-1 Promotes Coagulation, Which Is Necessary for Protective Immunity in the Lung Against Streptococcus pneumoniae Infection

Interleukin (IL)-1 is a well-known cytokine for the initiation of innate immunity in bacterial infection. However, the underlying mechanism of IL-1 on the respiratory infection is not fully elucidated. We studied how IL-1 contributes to the host defense against Streptococcus pneumoniae. IL-1R(-/-) mice showed high mortality, local cytokine storm, and substantial infiltrates in the lower respiratory tract after intratracheal challenge with S. pneumoniae. The IL-1-deficient condition did not suppress the propagation of bacteria in the lung, although the recruitment and the bacteria-killing ability of neutrophils (CD11b(+)Ly6C(+)Ly6G(+)) were not defective compared with wild-type mice. Unexpectedly, we found that the transcription of fibrinogen alpha and gamma genes were highly activated in the lungs of wild-type mice after the infection, whereas no significant changes were found in IL-1R(-/-) mice. Of note, synthesis of fibrinogen was dependent on the IL-1-IL-6-Stat3 cascade. Treatment with recombinant fibrinogen improved survival and bacterial propagation in the IL-1R(-/-) mice and blockade of the coagulation increased the susceptibility of wild-type mice to pneumococcal pneumonia. Our findings suggest that IL-1 signaling leads to the synthesis of fibrinogen in the lung after pneumococcus infection and is followed by coagulation, which contributes to the control of bacterial infection in the pulmonary tract.

Three Independent Determinants of Protein Evolutionary Rate

One of the most widely accepted ideas related to the evolutionary rates of proteins is that functionally important residues or regions evolve slower than other regions, a reasonable outcome of which should be a slower evolutionary rate of the proteins with a higher density of functionally important sites. Oddly, the role of functional importance, mainly measured by essentiality, in determining evolutionary rate has been challenged in recent studies. Several variables other than protein essentiality, such as expression level, gene compactness, protein–protein interactions, etc., have been suggested to affect protein evolutionary rate. In the present review, we try to refine the concept of functional importance of a gene, and consider three factors—functional importance, expression level, and gene compactness, as independent determinants of evolutionary rate of a protein, based not only on their known correlation with evolutionary rate but also on a reasonable mechanistic model. We suggest a framework based on these mechanistic models to correctly interpret the correlations between evolutionary rates and the various variables as well as the interrelationships among the variables.