Table of Contents
Oct 2018
Volume 28, Issue 10, Page 963-1014
About the Cover:  
Ming Tian 1 and Frederick W. Alt 1
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Activation Induced Cytidine Deaminase is a mutator that is essential for antibody diversification. A new study, recently reported in Cell Research , provides insights into the mechanism that guides the mutator to physiological targets.
Navin B. Ramakrishna 1,2 and M. Azim Surani 1,3
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By synchronizing the first wave of spermatogenesis, Chen and colleagues profile gene levels and regulation dynamics in 20 stages of sperm development. From this, newfound molecular signatures of sperm maturation are unearthed and validated.
Yongbo Liu 1, Hua-Bing Li 1 and Richard A. Flavell 2,3
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Cyclic GMP-AMP synthase (cGAS) is activated by DNA through direct binding. Active cGAS catalyzes the production of cyclic GMP-AMP (cGAMP), and consequently activates the innate immune responses. However, the detailed biological processes are poorly understood. Du and Chen demonstrated in a recent paper published on Science that DNA binding to cGAS robustly induced the formation of liquid like droplets in which cGAS was activated.
Zhenji Gan 1, Tingting Fu 1 , Daniel P. Kelly 2 and Rick B. Vega 3
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Skeletal muscle fitness and plasticity is an important determinant of human health and disease. Mitochondria are essential for maintaining skeletal muscle energy homeostasis by adaptive re-programming to meet the demands imposed by a myriad of physiologic or pathophysiological stresses. Skeletal muscle mitochondrial dysfunction has been implicated in the pathogenesis of many diseases, including muscular dystrophy, atrophy, type 2 diabetes, and aging-related sarcopenia. Notably, exercise counteracts the effects of many chronic diseases on skeletal muscle mitochondrial function. Recent studies have revealed a finely tuned regulatory network that orchestrates skeletal muscle mitochondrial biogenesis and function in response to exercise and in disease states. In addition, increasing evidence suggests that mitochondria also serve to “communicate” with the nucleus and mediate adaptive genomic re-programming. Here we review the current state of knowledge relevant to the dynamic remodeling of skeletal muscle mitochondria in response to exercise and in disease states.
Juan Chen 1,2, Zhaokui Cai 1,2, Meizhu Bai 3,4, Xiaohua Yu 1,2, Chao Zhang 5, Changchang Cao 1,2, Xihao Hu 1,2, Lei Wang 1,6, Ruibao Su 1,2,Di Wang 1,2, Lei Wang 1,2, Yingpeng Yao 7, Rong Ye 1,2, Baidong Hou 5, Yang Yu1, Shuyang Yu7, Jinsong Li3,4 and Yuanchao Xue1,2
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Activation-induced cytidine deaminase (AID) mediates class switching by binding to a small fraction of single-stranded DNA (ssDNA) to diversify the antibody repertoire. The precise mechanism for highly selective AID targeting in the genome has remained elusive. Here, we report an RNA-binding protein, ROD1 (also known as PTBP3), that is both required and sufficient to define AID-binding sites genome-wide in activated B cells. ROD1 interacts with AID via an ultraconserved loop, which proves to be critical for the recruitment of AID to ssDNA using bi-directionally transcribed nascent RNAs as stepping stones. Strikingly, AID-specific mutations identified in human patients with hyper-IgM syndrome type 2 (HIGM2) completely disrupt the AID interacting surface with ROD1, thereby abolishing the recruitment of AID to immunoglobulin (Ig) loci. Together, our results suggest that bi-directionally transcribed RNA traps the RNA-binding protein ROD1, which serves as a guiding system for AID to load onto specific genomic loci to induce DNA rearrangement during immune responses.
Bin Liu 1, Johan Palmfeldt 2, Lin Lin 3, Alexandria Colaço 1, Knut K. B. Clemmensen 1, Jinrong Huang 4,5,6, Fengping Xu 4,5,6, Xin Liu 4,6, Kenji Maeda 1, Yonglun Luo 3,4,6 and Marja Jäättelä 1,7
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Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment and increased acid production, cancer cells maintain alkaline intracellular pH that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration, and invasion. Here we identify signal transducer and activator of transcription-3 (STAT3) as a key factor in the preservation of alkaline cytosol. STAT3 associates with the vacuolar H+-ATPase in a coiled-coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing cytosolic pH and increasing lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild-type STAT3 or STAT3 mutants unable to activate target genes (Tyr705Phe and DNA-binding mutant) or to regulate mitochondrial respiration (Ser727Ala). Upon cytosolic acidification, STAT3 is transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium. These data reveal STAT3 as a regulator of intracellular pH and, vice versa, intracellular pH as a regulator of STAT3 localization and activity.
Zhe Yang 1,2, Rui Huang 3,4, Xin Fu 5,6,7, Gaohang Wang 1,2, Wei Qi 1,2, Decai Mao 8, Zhaomei Shi 5, Wei L. Shen 5 and Liming Wang 1,2
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Adequate protein intake is crucial for the survival and well-being of animals. How animals assess prospective protein sources and ensure dietary amino acid intake plays a critical role in protein homeostasis. By using a quantitative feeding assay, we show that three amino acids, L-glutamate (L-Glu), L-alanine (L-Ala) and L-aspartate (L-Asp), but not their D-enantiomers or the other 17 natural L-amino acids combined, rapidly promote food consumption in the fruit fly Drosophila melanogaster. This feeding-promoting effect of dietary amino acids is independent of mating experience and internal nutritional status. In vivo and ex vivo calcium imagings show that six brain neurons expressing diuretic hormone 44 (DH44) can be rapidly and directly activated by these amino acids, suggesting that these neurons are an amino acid sensor. Genetic inactivation of DH44+ neurons abolishes the increase in food consumption induced by dietary amino acids, whereas genetic activation of these neurons is sufficient to promote feeding, suggesting that DH44+ neurons mediate the effect of dietary amino acids to promote food consumption. Single-cell transcriptome analysis and immunostaining reveal that a putative amino acid transporter, CG13248, is enriched in DH44+ neurons. Knocking down CG13248 expression in DH44+ neurons blocks the increase in food consumption and eliminates calcium responses induced by dietary amino acids. Therefore, these data identify DH44+ neuron as a key sensor to detect amino acids and to enhance food intake via a putative transporter CG13248. These results shed critical light on the regulation of protein homeostasis at organismal levels by the nervous system.
Shuai Zong 1, Meng Wu 1, Jinke Gu 1, Tianya Liu 1, Runyu Guo 1 and Maojun Yang 1,2
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Respiration is one of the most basic features of living organisms, and the electron transport chain complexes are probably the most complicated protein system in mitochondria. Complex-IV is the terminal enzyme of the electron transport chain, existing either as randomly scattered complexes or as a component of supercomplexes. NDUFA4 was previously assumed as a subunit of complex-I, but recent biochemical data suggested it may be a subunit of complex-IV. However, no structural evidence supporting this notion was available till now. Here we obtained the 3.3 Å resolution structure of complex-IV derived from the human supercomplex I1III2IV1 and assigned the NDUFA4 subunit into complex-IV. Intriguingly, NDUFA4 lies exactly at the dimeric interface observed in previously reported crystal structures of complex-IV homodimer which would preclude complex-IV dimerization. Combining previous structural and biochemical data shown by us and other groups, we propose that the intact complex-IV is a monomer containing 14 subunits.
Hu Wang 1,2, Hongna Zuo 2, Jin Liu 1, Fei Wen 2, Yawei Gao 3,
Xudong Zhu 2, Bo Liu 1, Feng Xiao 1, Wengong Wang 4,Gang Huang 5
, Bin Shen 6 and Zhenyu Ju 1,2
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Dear Editor,

Hematopoietic stem cells (HSCs) have unique self-renewal capacity to replenish the entire blood system, which is essential for various stress conditions, such as serial transplantation, ionizing radiation, anti-cancer medication, hemorrhage or infection.1 N6-methyl-adenosine (m6A), the most prevalent reversible nucleotide modification in cellular mRNA in eukaryotes,2 is associated with the maturation, translation, and eventual decay of protein-coding transcripts.3,4 “Reader” proteins of m6A modification mediate many of the properties of m6A-methylated transcripts through methyl-specific RNA binding.5,6 Although the function of m6A modification in cell fate decision of embryonic stem cells and hematopoietic stem and progenitor cells (HSPCs) has been recently reported,7,8 the role of “Reader” proteins in HSC function has not been reported yet, especially under hematological stresses. It is of great importance to understand how HSCs recognize and respond to such modifications. Here, we investigated the “Reader” protein of m6A modification in HSC homeostasis and regeneration upon various stresses.
Zhongzhong Chen 1,2, Yunping Lei 3,4, Yufang Zheng 1,2,5,Vanessa Aguiar-Pulido 6, M. Elizabeth Ross 6, Rui Peng 1, Li Jin 1,2,Ting Zhang 7, Richard H. Finnell 3,4 and Hongyan Wang 1,2,8,9
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Dear Editor,

Neural tube defects (NTDs) are a class of major structural malformations affecting the brain and spinal cord. They are among the most common congenital anomalies with a worldwide prevalence of 0.1%.1,2 Elucidating the genetic basis of their complex etiology has eluded our best efforts to date. Although there are more than 400 genes capable of producing an NTD phenotype when mutated in the mouse,3,4 studies of human candidate genes based on mouse NTD genes have not been informative, except for genes in the planar cell polarity pathway.5 Recently, an omnigenic model of inheritance was proposed for complex traits, suggesting that the associated signals tend to spread across almost the entire genome.6 In light of this new perspective on the genomic architecture of complex traits, we re-evaluated whole-genome sequencing (WGS) data from three different NTD cohorts (Han Chinese, Caucasian USA, and Middle Eastern/Qatar).



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