1.Shu-szi Sin: A Chinese pioneer biologist, ancient agronomist, and educator.
Qun XIE ; Yan-Ping CHENG ; Lei FU
Protein & Cell 2021;12(7):515-517
3.Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network.
Yu-Kun XIA ; Yi-Rong ZENG ; Meng-Li ZHANG ; Peng LIU ; Fang LIU ; Hao ZHANG ; Chen-Xi HE ; Yi-Ping SUN ; Jin-Ye ZHANG ; Cheng ZHANG ; Lei SONG ; Chen DING ; Yu-Jie TANG ; Zhen YANG ; Chen YANG ; Pu WANG ; Kun-Liang GUAN ; Yue XIONG ; Dan YE
Protein & Cell 2021;12(7):557-577
Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
4.Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2.
Xiaoying CHEN ; Xu HAN ; Bruno BLANCHI ; Wuqiang GUAN ; Weihong GE ; Yong-Chun YU ; Yi E SUN
Protein & Cell 2021;12(8):639-652
Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2-deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.
6.Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy.
Pranavi KOPPULA ; Li ZHUANG ; Boyi GAN
Protein & Cell 2021;12(8):599-620
The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11
7.Lipids and membrane-associated proteins in autophagy.
Linsen LI ; Mindan TONG ; Yuhui FU ; Fang CHEN ; Shen ZHANG ; Hanmo CHEN ; Xi MA ; Defa LI ; Xiaoxia LIU ; Qing ZHONG
Protein & Cell 2021;12(7):520-544
Autophagy is essential for the maintenance of cellular homeostasis and its dysfunction has been linked to various diseases. Autophagy is a membrane driven process and tightly regulated by membrane-associated proteins. Here, we summarized membrane lipid composition, and membrane-associated proteins relevant to autophagy from a spatiotemporal perspective. In particular, we focused on three important membrane remodeling processes in autophagy, lipid transfer for phagophore elongation, membrane scission for phagophore closure, and autophagosome-lysosome membrane fusion. We discussed the significance of the discoveries in this field and possible avenues to follow for future studies. Finally, we summarized the membrane-associated biochemical techniques and assays used to study membrane properties, with a discussion of their applications in autophagy.
8.Repurposing FDA-approved drugs for SARS-CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interaction.
Wenyu FU ; Yujianan CHEN ; Kaidi WANG ; Aubryanna HETTINGHOUSE ; Wenhuo HU ; Jing-Quan WANG ; Zi-Ning LEI ; Zhe-Sheng CHEN ; Kenneth A STAPLEFORD ; Chuan-Ju LIU
Protein & Cell 2021;12(7):586-591
9.Roles of Tet2 in meiosis, fertility and reproductive aging.
Huasong WANG ; Linlin LIU ; Mo GOU ; Guian HUANG ; Chenglei TIAN ; Jiao YANG ; Haiying WANG ; Qin XU ; Guo Liang XU ; Lin LIU
Protein & Cell 2021;12(7):578-585
10.Structural insights into the activation initiation of full-length mGlu1.
Jinyi ZHANG ; Lu QU ; Lijie WU ; Xiaomeng TANG ; Feng LUO ; Weixiu XU ; Yueming XU ; Zhi-Jie LIU ; Tian HUA
Protein & Cell 2021;12(8):662-667