News & Comment

The use of genetic screens to define cellular pathways that regulate neurodegenerative disease proteins has emerged as a powerful strategy to identify potential therapeutic targets for these disorders. Using cross-species genetic screens, Park et al. recently identified RAS-MAPK-MSK1 as a cellular pathway that modulates levels of the polyglutamine-containing protein ATXN1 and its subsequent toxicity in SCA1.

Sirtuins have received a lot of attention in biological functions associated with metabolism, survival development, and most recently, neurodegeneration. The versatile role of sirtuins can be readily redirected for drug discovery studies for novel treatment in amyotrophic lateral sclerosis (ALS), as presented in this highlight, by sirtuin-mediated ketogenic responses influencing mitochondrial function.

The origin of the coronary vessels remains a mystery. Here we discuss recent studies that address this puzzle, including new work by Tian et al. recently published in Cell Research.

While M1 macrophages are highly pro-inflammatory and microbicidal, M2 macrophages and the related tumor associated macrophages (TAMs) regulate tissue remodeling and angiogenesis and can display immunomodulatory activity. In July issue of Cell Research, Zhang et al. show that ROS production, critical for the activation and functions of M1 macrophages, is necessary for the differentiation of M2 macrophages and TAMs, and that antioxidant therapy blocks TAM differentiation and tumorigenesis in mouse models of cancer.

Recent studies suggest that microRNA (miRNA) processing is a key regulatory step in the miRNA biogenesis as well as its transcriptional control. In a paper recently published in Nature, Shen et al. revealed that epidermal growth factor receptor (EGFR) directly interacts with argonaute 2 (AGO2), a critical component of RNA-induced silencing complex (RISC), and inhibits the maturation of specific tumor suppressive miRNAs under hypoxic condition.

Each subunit of voltage-gated cation channels comprises a voltage-sensing domain and a pore region. In a paper recently published in Cell Research, Li et al. showed that the gating charge pathway of the voltage sensor of the KCNQ2 K⁺ channel can accommodate small opener molecules and offer a new target to treat hyperexcitability disorders.

Although adult cardiac myocytes (CMs) have very little proliferative potential, fetal CMs divide robustly. The mechanisms underlying the post-mitotic state of CMs are poorly understood; however, recently Mahmoud et al. identified a homeodomain transcription factor, Meis1, which controls postnatal CM cell cycle.

A cyclic dinucleotide comprised of GMP and AMP was previously shown to be a key intermediate during activation of innate immune responses to cytosolic DNA. A report by Patel and Tuschl groups published in Cell reveals the structure of the enzyme involved in the synthesis of this second messenger and identifies this cyclic dinucleotide as a unique compound in metazoan cell signaling.

Oncogene-driven adaptation of metabolism during tumorigenesis includes steps that stimulate the uptake of nutrients, especially glucose and glutamine, to sustain cell growth and proliferation. Macropinocytosis, a clathrin- and caveolin-independent endocytotic process that had previously been linked to the action of oncogenic Ras and Src, is now shown to contribute to amino acid uptake via enhanced delivery of extracellular proteins to lysosomes.

In a recent paper published in Cell Research, an association between expression of mitochondrial aldehyde dehydrogenase (ALDH2), a mitochondrial chaperon expressed in the brain, and the prevalence of stroke is revealed. This finding indicates that ALDH2 may serve as a potential endogenous neuroprotective target and a promising therapeutic strategy for the management of stroke.

Recent studies have uncovered a specific role of TET proteins in reprogramming somatic cells to induced pluripotent stem cells, a process where O-linked β-N-acetylglucosamine transferase may play a crucial role.

Recently discovered recurrent somatic mutations in the key metabolic enzymes IDH1 and IDH2 produce the aberrant oncometabolite 2-HG and contribute to malignant transformation of hematopoietic and glial cells. Two recent reports in Science describe the first IDH1 and IDH2 mutant-specific small-molecule inhibitors, which induce cell differentiation of myeloid leukemias and malignant gliomas.

CG-rich DNA “reader” proteins that bind non-methylated CpG sequences have emerged as critical factors to the process of cell differentiation and development. In a recent paper in Nature, Ko et al. show that the CXXC domain protein, IDAX, plays a crucial role as a CG-rich DNA-binding factor in the regulation of Ten-Eleven-Translocation 2 (TET2) protein function.

A recent study published in Nature by Keestra and colleagues addresses how the immune system detects the pathogenic potential of microbes and provides evidence that one strategy involves NOD1, which monitors the activation state of the RhoGTPases that are targeted by virulence effectors produced by pathogenic microbes. Interestingly, their findings reveal striking similarities with previous observations made in flies and plants, establishing the evolutionary conservation of this detection system in the innate immune arsenal in many taxa.

Three recently published reports, including one in Cell Research, generated Ssb1 knockout mice and demonstrated critical roles of this protein in regulating skeletogenesis, telomere homeostasis and tumor suppression.

Two recent publications suggest that dietary salt may polarize TH17 cells and therefore increase the risk of developing autoimmune disease. Where low salt diets can readily be tested for their therapeutic effects in autoimmune disease, more work is needed to connect dietary salts with the development of immunopathology.