Research Highlights in 2013

Cand1 (Cullin-associated and neddylation-dissociated protein 1) has long been known as a regulator of SCF ubiquitin ligases, but details remained puzzling due to conflicting results from in vitro and in vivo experiments. Three recent reports, one in Cell and two in Nature Communications, propose Cand1 as a protein exchange factor with interesting mechanism that reconciles Cand1 genetics and biochemistry.

Small non-coding microRNAs (miRNAs, miRs) regulate gene expression in virtually all cells, and they have been implicated in cardiovascular disease and aging. In a paper recently published in Nature, miR-34a was identified as an aging-associated apoptotic and overall damaging factor for the heart.

The casein kinase 1 (CK1) family, a major intracellular serine/threonine kinase, is implicated in multiple pathways; however, understanding its regulation has proven challenging. A recent study published in Science identifying allosteric activation of CK1 by the DEAD-box RNA helicase DDX3 expands our understanding of the control of this abundant kinase family.

FBW7 tumor suppressor suppresses the growth and survival of tumor cells by promoting the degradation of several oncoproteins, and induces endothelial differentiation by modulating the NF1/RAS axis. A recent study in this issue of Cell Research showed that FBW7 further regulates endothelial functions via degrading transcription factor KLF2.

In mice treated with antibiotics to deplete commensal microbiota, there is a significant overhaul of host cellular disposition and function with CX3CR1+ mononuclear phagocytic cells carrying pathogenic and non-pathogenic administered bacteria to the (messenteric lymph node) MLN, resulting in T cell stimulation and IgA production.

Two recent papers in Science illustrate how the prokaryotic CRISPR-Cas immune system machinery, which typically targets invasive genetic elements such as viruses and plasmids, can be converted into a sophisticated molecular tool for next-generation human genome editing. The versatile Cas9 RNA-guided endonuclease can be readily reprogrammed using customizable small RNAs for sequence-specific single- or double-stranded DNA cleavage.

Paramyxoviruses evade antiviral immune response using a small nonstructural protein, V, which binds to the host dsRNA sensor MDA5 and prevents it from activating the interferon signaling pathway. A recent crystal structure of the V protein in complex with MDA5, published in Science, revealed that V disrupts the structure of MDA5 and is integrated into the MDA5 protein fold, providing an intriguing new example of viral mimicry as a countermeasure against the host immune system.

Emerging evidence suggests that the ability of p53 to regulate metabolism is important for its tumor suppressor activity. A recent study published in Nature reveals a novel connection between p53 and metabolism: p53 transcriptionally represses the expression of malic enzymes and associated NADPH production, which in turn triggers a positive feedback loop resulting in sustained p53 activation, cellular senescence, and tumor suppression.

The intracellular levels of the p53 tumor suppressor protein are regulated through various pathways and involve numerous regulatory components. A recent study published in Cell Research identifies a proteasome-independent pathway of p53 protein degradation in the nucleolus that is dependent on Def and Calpain3.

Allergic asthma is an inflammatory disease of the airways in which epithelial cells, dendritic cells and innate lymphoid cells are increasingly implicated. Recent findings suggest that apoptotic cells are phagocytosed by airway epithelial cells in a Rac1-dependent manner and this leads to dampening of innate and adaptive immunity to allergens.

In two recent reports in Science, James Chen and colleagues provide compelling evidence that detection of cytosolic DNA triggers the production of a novel second messenger, cyclic GMP-AMP (cGAMP), which in turn activates a signaling pathway that induces type I interferons (IFNs) in a STING-dependent manner. They further unravel a key role for a so far uncharacterized murine protein E330016A19 (human homolog: C6ORF150), now termed cGAMP synthetase (cGAS), to act as the DNA sensor that generates cGAMP.

Microglia were previously attributed to be vital brain guardians for neuronal survival and synaptic pruning during development as well as for the brain's fight against environmental pathogens. A new report in Nature by the Heneka, Latz and Golenbock groups, however, sheds new light on these distinct myeloid cells by revealing their deadly nature for mature neurons during neurodegeneration.

Successful derivation of pancreatic progenitors from human embryonic stem cells (hESCs) in vitro and further differentiation towards functional β cells in vivo may create the possibility of using hESC-derived pancreatic progenitors (PPs), instead of derived β cells, as an alternative transplantable source in β cell replacement therapy. Here we discuss present approaches, as well as future alternatives, in the fields of basic and clinic research on β cell differentiation, derivation and transplantation.

Maintenance of hematopoietic stem cells (HSCs) in vitro has been believed to be difficult due to a lack of complete understanding of HSC quiescence maintained by the niche. Recent evidence suggests that in vitro maintenance of human and mouse long-term HSCs (LT-HSCs) is possible through dual inhibition (2i) of both GSK-3 and mTOR in the absence of cytokines, serum, or feeder cells.

Protein homeostasis in higher eukaryotes is balanced by a dynamic network of adaptive mechanisms, including the unfolded protein response (UPR) and autophagy. In a paper recently published in Cell Research, Zhu and co-workers uncover a novel biological function of the unspliced form of the UPR transcription factor XBP1 in the modulation of autophagy through the control of FoxO1 turnover.

The transcription factor Foxp3 plays an indispensible role in the differentiation of regulatory T (Treg) cells and the expression of their suppressive functions. In a recent article published in Nature, Ouyang et al. demonstrate that Treg cell differentiation is also enabled by transcriptional networks controlled by another Forkhead box family member, Foxo1.

Why stem cell numbers decline with age is a major question in regenerative biology and medicine. Skeletal muscle has emerged as a powerful paradigm to address this issue. Recently, genetic and cell marking strategies were used to uncover a new and causal relationship between muscle stem cells and differentiated fibers that constitute their niche and provoke their loss.