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2017 Vol. 8, No. 1

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Recollection
The development of Chinese population genetics by Ruofu Du
Chongfeng Xu, Ziyuan Duan
2017, 8(1): 1-3. doi: 10.1007/s13238-016-0265-6
[Abstract](230) [PDF 556KB](816)
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Reviews
Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease
Xuelin Zhang, Yang Wang, Pingsheng Liu
2017, 8(1): 4-13. doi: 10.1007/s13238-016-0327-9
[Abstract](377) [PDF 498KB](2226)
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is an epidemic metabolic condition driven by an underlying lipid homeostasis disorder. The lipid droplet (LD), the main organelle involved in neutral lipid storage and hydrolysis, is a potential target for NAFLD therapeutic treatment. In this review, we summarize recent progress elucidating the connections between LD-associated proteins and NAFLD found by genome-wide association studies (GWAS), genomic and proteomic studies. Finally, we discuss a possible mechanism by which the protein 17β-hydroxysteroid dehydrogenase 13 (17β-HSD13) may promote the development of NAFLD.
Dual role for the unfolded protein response in the ovary: adaption and apoptosis
Ning Huang, Yang Yu, Jie Qiao
2017, 8(1): 14-24. doi: 10.1007/s13238-016-0312-3
[Abstract](247) [PDF 881KB](1609)
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The endoplasmic reticulum (ER) is the principal organelle responsible for several specific cellular functions including synthesis and folding of secretory or membrane proteins, lipid metabolism, and Ca2+ storage. Different physiological as well as pathological stress conditions can, however, perturb ER homeostasis, giving rise to an accumulation of unfolded or misfolded proteins in the ER lumen, a condition termed ER stress. To deal with an increased folding demand, cells activate the unfolded protein response (UPR), which is initially protective but can become detrimental if ER stress is severe and prolonged. Accumulating evidence demonstrates a link between the UPR and ovarian development and function, including follicular growth and maturation, follicular atresia, and corpus luteum biogenesis. Additionally, ER stress and the UPR may also play an important role in the ovary under pathological conditions. Understanding the molecular mechanisms related to the dual role of unfolded protein response in the ovarian physiology and pathology may reveal the pathogenesis of some reproductive endocrine diseases and provide a new guidance to improve the assisted reproductive technology. Here we review the current literature and discuss concepts and progress in understanding the UPR, and we also analyze the role of ER stress and the UPR in the ovary.
Research articles
Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy
Mengqi Lv, Chongyuan Wang, Fudong Li, Junhui Peng, Bin Wen, Qingguo Gong, Yunyu Shi, Yajun Tang
2017, 8(1): 25-38. doi: 10.1007/s13238-016-0328-8
[Abstract](210) [PDF 2622KB](2913)
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Mitophagy is an essential intracellular process that eliminates dysfunctional mitochondria and maintains cellular homeostasis. Mitophagy is regulated by the post-translational modification of mitophagy receptors. Fun14 domain-containing protein 1 (FUNDC1) was reported to be a new receptor for hypoxia-induced mitophagy in mammalian cells and interact with microtubule-associated protein light chain 3 beta (LC3B) through its LC3 interaction region (LIR). Moreover, the phosphorylation modification of FUNDC1 affects its binding affinity for LC3B and regulates selective mitophagy. However, the structural basis of this regulation mechanism remains unclear. Here, we present the crystal structure of LC3B in complex with a FUNDC1 LIR peptide phosphorylated at Ser17 (pS17), demonstrating the key residues of LC3B for the specific recognition of the phosphorylated or dephosphorylated FUNDC1. Intriguingly, the side chain of LC3B Lys49 shifts remarkably and forms a hydrogen bond and electrostatic interaction with the phosphate group of FUNDC1 pS17. Alternatively, phosphorylated Tyr18 (pY18) and Ser13 (pS13) in FUNDC1 significantly obstruct their interaction with the hydrophobic pocket and Arg10 of LC3B, respectively. Structural observations are further validated by mutation and isothermal titration calorimetry (ITC) assays. Therefore, our structural and biochemical results reveal a working model for the specific recognition of FUNDC1 by LC3B and imply that the reversible phosphorylation modification of mitophagy receptors may be a switch for selective mitophagy.
TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence
Lucy Cassar, Craig Nicholls, Alex R. Pinto, Ruping Chen, Lihui Wang, He Li, Jun-Ping Liu
2017, 8(1): 39-54. doi: 10.1007/s13238-016-0322-1
[Abstract](171) [PDF 3300KB](2202)
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Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRⅡ receptor-and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRⅡ receptor, but not TGFbRⅡ, ACTRⅡA or ACTRⅡB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRⅡ receptor-and Smad3-mediated repression of the hTERT gene.
LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation
Ruiqing Yan, Zhihua Liu
2017, 8(1): 55-66. doi: 10.1007/s13238-016-0326-x
[Abstract](263) [PDF 1027KB](1918)
Abstract:
The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn's disease, leprosy and familial Parkinson's disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.
Letters
Domain interactions of C-terminal Src Kinase determined through NMR spectroscopy with segmental isotope labeling
Dongsheng Liu, Ya Yuan, Rong Xu, David Cowburn
2017, 8(1): 67-71. doi: 10.1007/s13238-016-0333-y
[Abstract](215) [PDF 757KB](1105)
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Structural and functional analyses of human DDX41 DEAD domain
Yan Jiang, Yanping Zhu, Weicheng Qiu, Yong-Jun Liu, Genhong Cheng, Zhi-Jie Liu, Songying Ouyang
2017, 8(1): 72-76. doi: 10.1007/s13238-016-0351-9
[Abstract](262) [PDF 1091KB](1507)
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Erratum
Erratum to: Questions about NgAgo
Shawn Burgess, Linzhao Cheng, Feng Gu, Junjiu Huang, Zhiwei Huang, Shuo Lin, Jinsong Li, Wei Li, Wei Qin, Yujie Sun, Zhou Songyang, Wensheng Wei, Qiang Wu, Haoyi Wang, Xiaoqun Wang, Jing-Wei Xiong, Jianzhong Xi, Hui Yang, Bin Zhou, Bo Zhang
2017, 8(1): 77-77. doi: 10.1007/s13238-016-0349-3
[Abstract](215) [PDF 288KB](1502)
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