Research Highlights in 2017

G protein-coupled receptors (GPCRs) are ubiquitous gatekeepers of cellular response and signal predominantly by recruitment and activation of G proteins. In a recent paper in Nature, Flock et al. use large-scale bioinformatics to build a model of GPCR-G protein selectivity and an interactive database to interrogate potential receptor-G protein interactions.

Membrane transporter proteins are critical for cellular uptake and export of molecules, and are reported to function by a number of different molecular mechanisms. The new occluded state structure of the uracil transporter, UraA, from Escherichia coli, reveals that both coordinated movement of the two domains of a single protomer together with dimer formation are important for transport activity.

Recently, a Legionella pneumophila effector protein was shown to have an unprecedented ATP-independent ubiquitin ligase activity that couples phosphoribosylated ubiquitin (PR-Ub) to serine residues of host proteins. A new study published in Cell Research by Qiu et al. reveals that another Legionella effector protein, SidJ, catalyzes deubiquitination of PR-Ub by cleavage of the substrate-linked phosphodiester bond.

5-methylcytosine was shown before to be an epitranscriptomic mark. Yang et al. now explored the unique topology of this mRNA modification, identified its writer and demonstrated its involvement in nuclear-cytoplasmic shuttling mediated by a specific reader.

Chemotherapy is a predominant strategy to treat cancer and is often associated with toxicities like severe diarrhea that puts patients at additional risk and can hinder treatment strategies. Lian et al. recently explored the immune-mediated mechanisms of Irinotecan-induced diarrhea in colorectal cancer and found that double-stranded DNA in small vesicles can launch inflammation pathways in immune cells through the cytosolic DNA sensor AIM2.

Exosome-mediated intercellular communication has become an emerging field of human health and diseases. A recent study published by Cell Research reports that in zebrafish neurons can remotely regulate blood-brain barrier integrity by delivering miR-132 through secretion of exosomes.

Activation of the receptor interacting serine/threonine kinase (RIPK) 3 mediates an inflammatory type of cell death called necroptosis; in addition, RIPK3 has necroptosis-independent roles in inflammation, although these are not well defined. In a recent study published in Cell, Daniels and colleagues demonstrate that RIPK3 controls West Nile virus infection by promoting neuroinflammation in the central nervous system without affecting neuronal death.

Circular RNAs (circRNAs) were only recently discovered as a new class of noncoding RNAs, functionally still largely uncharacterized. Three publications that appeared concurrently in Cell Research and Molecular Cell provide initial evidence for certain endogenous circRNAs coding for proteins.

There has been a long-standing controversy of whether megakaryocytes release platelets in the marrow or travel to the lungs and release platelets there. Using two-photon electron microscopy and orthotopic lung transplantation, Lefrançais et al. now document that platelet release occurs physiologically in the lungs of mice from extrapulmonary megakaryocytes and that this release accounts for ∼50% of total platelet production.

Researchers at the University of Cambridge, UK have succeeded in reconstructing mouse embryos by combining pluripotent embryonic and multipotent trophoblast stem cells in a 3D scaffold; the study from the laboratory of Professor Zernicka-Goetz, recently published in Science, provides a break-through tool to probe early mammalian development outside the uterus. Achieving a similar feat with human cells might necessitate reconsideration of the 14-day rule as a limitation of such research.

Single Lgr5⁺ intestinal stem cells (ISCs) can be expanded in vitro into epithelial organoids or “mini-guts”, self-organizing cellular structures that recreate the intestinal differentiation program; Paneth cells, which constitute the intestinal stem cell niche, secrete stem cell growth signals, and are thus essential for this process. In a recent paper published in Nature, Rodríguez-Colman et al. describe how Paneth cells may be supporting the metabolic state of ISCs.

Tumor-associated macrophages (TAMs) contribute to breast cancer progression and dissemination; TAM-targeting strategies aimed at their reprogramming show promising preclinical results. In a new report Guerriero and colleagues demonstrate that a novel HDAC Class IIa inhibitor, TMP195, can reprogram monocytes and macrophages in the tumor into cells able to sustain a robust CD8 T cell-mediated anti-tumoral immune response.

The multimodular adapter p62/sequestosome-1 plays prominent roles in physiology and disease by mediating cell signaling and cargo degradation. The work by Peng et al. published recently in Cell Research provides mechanistic insights into activation of its autophagy receptor function critical for maintaining cell homeostasis during various forms of stress.

Infections with Zika virus are strongly associated with complications such as congenital microcephaly and can trigger Guillain-Barré syndrome in humans, highlighting the urgent need for a safe, efficacious vaccine as a preventative countermeasure. In a recent paper published in Cell, Richner et al. generated a lipid nanoparticle encapsulated modified mRNA vaccine encoding the prM and E genes from Zika virus, which showed protection and sterilizing immunity in immunocompetent mice.

High levels of endogenously generated DNA damage drive oncogenesis, sustain malignant progression and increase therapy resistance. In a paper recently published in Cell Research, Liu and colleagues added additional insights into this topic by uncovering a novel intrinsic source of double-strand breaks that fosters the aggressiveness and stemness of malignant cells.

The consumption of exogenous free fatty acids by tissue-resident memory T (T_rm) cells is critical for their long-term survival and antiviral function, and appears to be a conserved feature of T_rm cells in both mouse and man, a recent paper published in Nature demonstrates.

In a new paper in Cell Research, Ji et al. find that transcription factor-instigated opening of chromatin, during cell reprogramming, can be sensed by the Baf60b-containing chromatin remodeling complex, which then activates the ATM-p53 pathway, leading to cell death. These findings from reprogramming studies unveil what I term a “chromatin remodeling checkpoint” whereby extensive, inappropriate chromatin opening events lead to cell elimination, thus preventing cell fate conversion that might occur upon tissue damage; if unchecked, such conversion could lead to metaplasia and cancer.

After injury and in disease of the central nervous system (CNS), local cells called astrocytes respond with diverse molecular changes whose functional consequences are incompletely understood. A combined genomic and experimental analysis shows that classically-activated microglia, which are innate immune cells resident in CNS neural tissue, release molecules that drive astrocytes into a neurotoxic state, raising important questions about potential adaptive and maladaptive functions of such a mechanism.

Long non-coding RNAs (lncRNAs) belong to the ever-increasing number of transcripts that are thought not to encode proteins. A recent study has now identified a small polypeptide encoded by the lncRNA LINC00961 that inhibits amino acid-induced mTORC1 activation in skeletal muscle.

Transcriptional activator-like effectors (TALEs) have emerged as powerful tools for genome editing. A recent study published by Cell Research reports that fusion of thioredoxin to TALEs unlocks their full potential in live-cell imaging to accurately analyze genome instability, telomere attrition and epigenetic alterations that are hallmarks of aging.