Research Highlights in 2014

RIG-I belongs to a type of intracellular pattern recognition receptors involved in the recognition of viral RNA by the innate immune system. A report by Peisley et al. published in Nature provides the crystal structure of human RIG-I revealing a tetrameric architecture of the RIG-I 2-CARD domain bound by three K63-linked ubiquitin chains, uncovering its activation mechanism for downstream signaling.

Akt phosphorylation at S473 and T308 has been believed to be the prerequisites for its activation for years. Now, new phosphorylation event on Akt is identified and can trigger Akt activation and lead to its downstream oncogenic events.

Long noncoding RNAs (lncRNAs) are emerging as important functional components in the establishment of long-range chromosomal interactions. In a recent paper published in Cell Research, Xiang et al. provide mechanistic insight into this phenomenon by characterizing the role of CCAT1-L, a colorectal cancer-specific lncRNA, in intra-chromosome looping between the MYC gene promoter and distal upstream enhancer elements that regulate MYC transcription.

Generation of neural progenitor cells (NPCs) from pluripotent stem cells including ESCs and iPSCs and derivation of NPCs from somatic tissues have been considered promising approaches that could be used therapeutically to restore function in patients suffering neurodegenerative diseases. A new study published in Cell Research shows, for the first time, the generation of NPCs from somatic cells by small molecule compounds under hypoxia without exogenous transcription factors.

Regulatory information stored in modified histones is functionally translated by effector proteins ('readers'), which identify the histone mark to determine the specificity of the response. A recent study identifying the tumor suppressor protein ZMYND11 as an exclusive reader of methylated histone variant H3.3, throws light on the role of transcription regulation in suppressing tumors.

In a recent study published in Nature, Warren et al. describe the generation of a novel synthetic adenosine analogue, BCX4430, a synthetic drug-like small molecule that provides protection from Ebola and Marburg virus infection in animal models.

The way in which the DNA damage response signals the presence of DNA lesions and mediates DNA repair has not been fully elucidated. Now, Gao et al. reveal that diRNA-Ago2 complexes recruit RAD51 to the break sites.

The high variability and the limited knowledge of the structure of the hepatitis C virus (HCV) envelope glycoproteins (GP) are challenging hurdles for vaccine design. Recently, Kong et al. published a new model of HCV E2 GP structure in Science, revealing a globular structure, starkly contrasting from the extended model of class II fusion proteins from other Flaviviridae viruses.

Bone-lining osteolineage cells were previously implicated as contributors to hematological disorders and malignancies. A recent report in Nature now demonstrates that a specific mutation in mouse collagen-expressing osteoblastic cells leads to MDS and AML with 100% penetrance and is associated with strikingly similar findings in human patients.

Mitochondrial genes including Mfn2 are at the center of many diseases, underscoring their potential as a therapeutical target. The Chen group now identified 15-oxospiramilactone as a chemical inhibitor of the mammalian deubiquitylase USP30, acting on Mfn1 and Mfn2.

In a recent issue of Nature, Kumar et al. demonstrate that the oncogenic potential of the Hmga2 gene is largely due to the ability of its transcript to operate as a competing endogenous RNA in a protein coding-independent manner. The Hmga2 mRNA decoys the let-7 microRNA family to regulate Tgfbr3 expression and enhance TGF-β signaling, thereby promoting lung cancer progression.

Chemical modifications of histone proteins directly and indirectly affect chromatin structure and thereby contribute to the multilayered control of diverse DNA-based processes. A recent study in Nature enriches this list of enzyme-dependent posttranslational histone marks by H2A glutamine methylation that appears to be dedicated to only one specific cellular process, the regulation of nucleolar rDNA transcription.

DNA methylation is a fundamental epigenetic mechanism governing regulation of gene expression during mammalian development. A recent study published in Nature shows a novel long noncoding RNA (lncRNA) arising from the CEBPA gene locus (termed ecCEBPA) that is critical for regulation of DNA methylation at this site through the association of ecCEBPA with DNA methyltransferase 1, DNMT1.

The Hippo pathway is a signal transduction pathway that regulates organ growth, stem cell biology, regeneration and cancer. Three recent proteomic studies with Hippo pathway components uncovered extensive networks of interacting proteins revealing novel connections to cell-cell junctions, regulation by vesicle trafficking, and phosphorylation-dependent remodeling of the interactome, and provide a rich landscape of novel interactors ripe for mechanistic studies.

Recent data from two independent laboratories have shed new light on the molecular mechanisms by which mixed lineage kinase domain-like (MLKL) promotes a peculiar form of regulated necrosis known as necroptosis. Upon phosphorylation by receptor-interacting protein kinase 3 (RIPK3), MLKL appears indeed to form oligomers that localize to the plasma membrane and compromise its ability to preserve ionic homeostasis.

A recent study published in Immunity shows that foreign antigens elicit all-or-nothing T cell responses and that a single antigen is enough to trigger this digital cytokine secretion.