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2018 Vol. 9, No. 9

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Base editors which enable highly efficient nucleotide
substitutions without inducing DNA double-strand breaks have
promising potential applications in various fields. In this issue
of Protein & Cell, two independent groups demonstrated highly
efficient “A” to “G” conversions in mouse and rat embryos
using the adenine base editor (ABE) technology. With the
help of this powerful tool, Liang et al. successfully generated
a new mouse Dunchenne muscular dystrophy (DMD) model
by mutating the base pairs involved in DMD gene mRNA
splicing. In addition to making mouse and rat models using the
ABE technology, Yang et al. reported expansion of the ABE
targeting scope by fusion of the edTadA with different Cas9
variants. Moreover, they also demonstrated their method
of increasing the ABE efficiency via using the chemically
modified guide RNAs.
Recollection
Old Master Zhu: in memory of virologist Guan-Fu Zhu
Qing Ye, Tao Jiang, Cheng-Feng Qin
2018, 9(9): 749-751. doi: 10.1007/s13238-017-0396-4
[Abstract](121) [PDF 658KB](830)
Abstract:
Highlight
Adenine base editing to mimic or correct disease mutations in rodents
Ruotong Ren, Juan Carlos Izpisua Belmonte, Guang-Hui Liu
2018, 9(9): 752-753. doi: 10.1007/s13238-018-0570-3
[Abstract](200) [PDF 310KB](731)
Abstract:
Review
The role of ubiquitination and deubiquitination in the regulation of cell junctions
Junting Cai, K. Miranda Culley, Yutong Zhao, Jing Zhao
2018, 9(9): 754-769. doi: 10.1007/s13238-017-0486-3
[Abstract](337) [FullText HTML] (130) [PDF 1482KB](1815)
Abstract:
Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a variety of human disorders, such as inflammatory diseases and cancers. Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases. Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability, receptor internalization, enzyme activity, and protein-protein interactions. Ubiquitination is tightly regulated by ubiquitin E3 ligases and can be reversed by deubiquitinating enzymes. Recent studies have been focusing on investigating the effect of protein stability in the regulation of cell-cell junctions. Ubiquitination and degradation of cadherins, claudins, and their interacting proteins are implicated in epithelial and endothelial barrier disruption. Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases' biological activities. Taken together these studies, ubiquitination plays a critical role in modulating cell junctions and motility. In this review, we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions, including junction proteins, their interacting proteins, and small Rho GTPases. We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiquitination on human disorders caused by dysfunction of cell junctions.
Research articles
Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway
Li Yang, Jing Chen, Xiaoyan Han, Enfan Zhang, Xi Huang, Xing Guo, Qingxiao Chen, Wenjun Wu, Gaofeng Zheng, Donghua He, Yi Zhao, Yang Yang, Jingsong He, Zhen Cai
2018, 9(9): 770-784. doi: 10.1007/s13238-017-0500-9
[Abstract](285) [PDF 3153KB](1006)
Abstract:
Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma (MM). While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 (Pirh2) in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factorkappaB (NF-κB) p65, pp65, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF-κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.
LRRC25 plays a key role in all-trans retinoic acid-induced granulocytic differentiation as a novel potential leukocyte differentiation antigen
Weili Liu, Ting Li, Pingzhang Wang, Wanchang Liu, Fujun Liu, Xiaoning Mo, Zhengyang Liu, Quansheng Song, Ping Lv, Guorui Ruan, Wenling Han
2018, 9(9): 785-798. doi: 10.1007/s13238-017-0421-7
[Abstract](262) [PDF 1987KB](1407)
Abstract:
Leukocyte differentiation antigens (LDAs) play important roles in the immune system, by serving as surface markers and participating in multiple biological activities, such as recognizing pathogens, mediating membrane signals, interacting with other cells or systems, and regulating cell differentiation and activation. Data mining is a powerful tool used to identify novel LDAs from whole genome. LRRC25 (leucine rich repeat-containing 25) was predicted to have a role in the function of myeloid cells by a large-scale "omics" data analysis. Further experimental validation showed that LRRC25 is highly expressed in primary myeloid cells, such as granulocytes and monocytes, and lowly/intermediately expressed in B cells, but not in T cells and almost all NK cells. It was down-regulated in multiple acute myeloid leukemia (AML) cell lines and bone marrow cells of AML patients and up-regulated after all-trans retinoic acid (ATRA)-mediated granulocytic differentiation in AML cell lines and acute promyelocytic leukemia (APL; AML-M3, FAB classification) cells. Localization analysis showed that LRRC25 is a type I transmembrane molecule. Although ectopic LRRC25 did not promote spontaneous differentiation of NB4 cells, knockdown of LRRC25 by siRNA or shRNA and knockout of LRRC25 by the CRISPR-Cas9 system attenuated ATRA-induced terminal granulocytic differentiation, and restoration of LRRC25 in knockout cells could rescue ATRA-induced granulocytic differentiation. Therefore, LRRC25, a potential leukocyte differentiation antigen, is a key regulator of ATRA-induced granulocytic differentiation.
Identification of new type I interferonstimulated genes and investigation of their involvement in IFN-β activation
Xiaolin Zhang, Wei Yang, Xinlu Wang, Xuyuan Zhang, Huabin Tian, Hongyu Deng, Liguo Zhang, Guangxia Gao
2018, 9(9): 799-807. doi: 10.1007/s13238-018-0511-1
[Abstract](319) [PDF 740KB](1213)
Abstract:
Virus infection induces the production of type I interferons (IFNs). IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes (ISGs). ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production. We used consensus interferon (Con-IFN), an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells. Microarray analysis was employed to identify those genes whose expressions were up-regulated. Six hundred and seventeen genes were up-regulated more than 3-fold. Out of these 617 genes, 138 were not previously reported as ISGs and thus were further pursued. Validation of these 138 genes using quantitative reverse transcription PCR (qRT-PCR) confirmed 91 genes. We screened 89 genes for those involved in Sendai virus (SeV)-induced IFN-β promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-β activation. We provide evidence indicating that PIM1 specifically inhibits RIG-I-and MDA5-mediated IFN-β signaling. Our results expand the ISG library and identify PIM1 as an ISG that participates in the regulation of virus-induced type I interferon production.
Letters
Effective and precise adenine base editing in mouse zygotes
Puping Liang, Hongwei Sun, Xiya Zhang, Xiaowei Xie, Jinran Zhang, Yaofu Bai, Xueling Ouyang, Shengyao Zhi, Yuanyan Xiong, Wenbin Ma, Dan Liu, Junjiu Huang, Zhou Songyang
2018, 9(9): 808-813. doi: 10.1007/s13238-018-0566-z
[Abstract](348) [PDF 1419KB](998)
Abstract:
Increasing targeting scope of adenosine base editors in mouse and rat embryos through fusion of TadA deaminase with Cas9 variants
Lei Yang, Xiaohui Zhang, Liren Wang, Shuming Yin, Biyun Zhu, Ling Xie, Qiuhui Duan, Huiqiong Hu, Rui Zheng, Yu Wei, Liangyue Peng, Honghui Han, Jiqin Zhang, Wenjuan Qiu, Hongquan Geng, Stefan Siwko, Xueli Zhang, Mingyao Liu, Dali Li
2018, 9(9): 814-819. doi: 10.1007/s13238-018-0568-x
[Abstract](132) [PDF 1761KB](1207)
Abstract:
Long non-coding RNA tagging and expression manipulation via CRISPR/Cas9-mediated targeted insertion
Tian-Lin Cheng, Zilong Qiu
2018, 9(9): 820-825. doi: 10.1007/s13238-017-0464-9
[Abstract](199) [PDF 1091KB](2601)
Abstract:

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