Person:
Yuan, Junying

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Yuan

First Name

Junying

Name

Yuan, Junying

Filters

2009 - 200922010 - 202016

Settings

Author's Publications: search.filters.isAuthorOfPublication.c8e26337-1501-4870-b13d-952b08041583

Search Results

Now showing 1 - 10 of 18
  • Thumbnail Image
    Publication
    Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1
    (2014) Py, Bénédicte F.; Jin, Mingzhi; Desai, Bimal N.; Penumaka, Anirudh; Zhu, Hong; Kober, Maike; Dietrich, Alexander; Lipinski, Marta M.; Henry, Thomas; Clapham, David; Yuan, Junying
    SUMMARY Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1−/− mice show higher IL-1β secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.
  • Thumbnail Image
    Publication
    Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018
    (Nature Publishing Group UK, 2018) Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A.; Abrams, John M.; Adam, Dieter; Agostinis, Patrizia; Alnemri, Emad S.; Altucci, Lucia; Amelio, Ivano; Andrews, David W.; Annicchiarico-Petruzzelli, Margherita; Antonov, Alexey V.; Arama, Eli; Baehrecke, Eric H.; Barlev, Nickolai A.; Bazan, Nicolas G.; Bernassola, Francesca; Bertrand, Mathieu J. M.; Bianchi, Katiuscia; Blagosklonny, Mikhail V.; Blomgren, Klas; Borner, Christoph; Boya, Patricia; Brenner, Catherine; Campanella, Michelangelo; Candi, Eleonora; Carmona-Gutierrez, Didac; Cecconi, Francesco; Chan, Francis K.-M.; Chandel, Navdeep S.; Cheng, Emily H.; Chipuk, Jerry E.; Cidlowski, John A.; Ciechanover, Aaron; Cohen, Gerald M.; Conrad, Marcus; Cubillos-Ruiz, Juan R.; Czabotar, Peter E.; D’Angiolella, Vincenzo; Dawson, Ted M.; Dawson, Valina L.; De Laurenzi, Vincenzo; De Maria, Ruggero; Debatin, Klaus-Michael; DeBerardinis, Ralph J.; Deshmukh, Mohanish; Di Daniele, Nicola; Di Virgilio, Francesco; Dixit, Vishva M.; Dixon, Scott J.; Duckett, Colin S.; Dynlacht, Brian D.; El-Deiry, Wafik S.; Elrod, John W.; Fimia, Gian Maria; Fulda, Simone; García-Sáez, Ana J.; Garg, Abhishek D.; Garrido, Carmen; Gavathiotis, Evripidis; Golstein, Pierre; Gottlieb, Eyal; Green, Douglas R.; Greene, Lloyd A.; Gronemeyer, Hinrich; Gross, Atan; Hajnoczky, Gyorgy; Hardwick, J. Marie; Harris, Isaac; Hengartner, Michael O.; Hetz, Claudio; Ichijo, Hidenori; Jäättelä, Marja; Joseph, Bertrand; Jost, Philipp J.; Juin, Philippe P.; Kaiser, William J.; Karin, Michael; Kaufmann, Thomas; Kepp, Oliver; Kimchi, Adi; Kitsis, Richard N.; Klionsky, Daniel J.; Knight, Richard A.; Kumar, Sharad; Lee, Sam; Lemasters, John J.; Levine, Beth; Linkermann, Andreas; Lipton, Stuart A.; Lockshin, Richard A.; López-Otín, Carlos; Lowe, Scott W.; Luedde, Tom; Lugli, Enrico; MacFarlane, Marion; Madeo, Frank; Malewicz, Michal; Malorni, Walter; Manic, Gwenola; Marine, Jean-Christophe; Martin, Seamus J.; Martinou, Jean-Claude; Medema, Jan Paul; Mehlen, Patrick; Meier, Pascal; Melino, Sonia; Miao, Edward A.; Molkentin, Jeffery D.; Moll, Ute M.; Muñoz-Pinedo, Cristina; Nagata, Shigekazu; Nuñez, Gabriel; Oberst, Andrew; Oren, Moshe; Overholtzer, Michael; Pagano, Michele; Panaretakis, Theocharis; Pasparakis, Manolis; Penninger, Josef M.; Pereira, David M.; Pervaiz, Shazib; Peter, Marcus E.; Piacentini, Mauro; Pinton, Paolo; Prehn, Jochen H.M.; Puthalakath, Hamsa; Rabinovich, Gabriel A.; Rehm, Markus; Rizzuto, Rosario; Rodrigues, Cecilia M.P.; Rubinsztein, David C.; Rudel, Thomas; Ryan, Kevin M.; Sayan, Emre; Scorrano, Luca; Shao, Feng; Shi, Yufang; Silke, John; Simon, Hans-Uwe; Sistigu, Antonella; Stockwell, Brent R.; Strasser, Andreas; Szabadkai, Gyorgy; Tait, Stephen W.G.; Tang, Daolin; Tavernarakis, Nektarios; Thorburn, Andrew; Tsujimoto, Yoshihide; Turk, Boris; Vanden Berghe, Tom; Vandenabeele, Peter; Vander Heiden, Matthew; Villunger, Andreas; Virgin, Herbert W.; Vousden, Karen H.; Vucic, Domagoj; Wagner, Erwin F.; Walczak, Henning; Wallach, David; Wang, Ying; Wells, James A.; Wood, Will; Yuan, Junying; Zakeri, Zahra; Zhivotovsky, Boris; Zitvogel, Laurence; Melino, Gerry; Kroemer, Guido
    Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
  • Thumbnail Image
    Publication
    Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis
    (Nature Publishing Group UK, 2017) Geng, Jiefei; Ito, Yasushi; Shi, Linyu; Amin, Palak; Chu, Jiachen; Ouchida, Amanda Tomie; Mookhtiar, Adnan Kasim; Zhao, Heng; Xu, Daichao; Shan, Bing; Najafov, Ayaz; Gao, Guangping; Akira, Shizuo; Yuan, Junying
    Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.
  • Thumbnail Image
    Publication
    ABIN-1 Regulates RIPK1 Activation by Bridging M1 ubiquitination with K63 Deubiquitination in TNF-RSC
    (2017) Dziedzic, Slawomir A.; Su, Zhenyi; Barrett, Vica Jean; Najafov, Ayaz; Mookhitiar, Adnan K.; Amin, Palak; Pan, Heling; Sun, Li; Zhu, Hong; Ma, Averil; Abbott, Derek W.; Yuan, Junying
    Ubiquitination of TNFR1-signaling-complex (TNF-RSC) controls the activation of RIPK1, a kinase critically involved in mediating multiple TNFα activated deleterious events. However, the molecular mechanism that coordinates different types of ubiquitination modifications to regulate the activation of RIPK1 kinase remains unclear. Here, we show that ABIN-1/NAF-1, a ubiquitin-binding protein, is recruited rapidly into TNF-RSC in a manner dependent upon M1 ubiquitinating complex LUBAC to regulate the recruitment of A20 to control K63 deubiquitination of RIPK1. ABIN-1 deficiency reduces the recruitment of A20 and licenses cells to die through necroptosis by promoting K63 ubiquitination and activation of RIPK1 with TNFα stimulation under conditions that would otherwise exclusively activate apoptosis in wild-type cells. Inhibition of RIPK1 kinase and RIPK3 deficiency block the embryonic lethality of Abin-1−/− mice. We propose that ABIN-1 provides a critical link between M1 ubiquitination mediated by LUBAC complex and K63 deubiquitination by phospho-A20 to modulate the activation of RIPK1.
  • Thumbnail Image
    Publication
    Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1
    (Nature Publishing Group UK, 2018) Wang, Yu; Shan, Bing; Liang, Yaosi; Wei, Huiting; Yuan, Junying
    Parkin (Park2), a RING-between-RING-type E3 ubiquitin ligase, has been implicated in regulating NF-κB. Mutations in Parkin are associated with Parkinson’s disease. Here we investigated the interaction of Parkin with Receptor-interacting protein kinase 1 (RIPK1) kinase, a key mediator of multiple signaling pathways activated by TNFR1 including NF-κB pathway. We report that Parkin interacts with RIPK1 and mediates K63 ubiquitination of RIPK1 on K376 in TNFR1-signaling pathway. The expression of Parkin promotes the recruitment of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), nuclear factor-κB (NF-κB) essential molecule (NEMO), Sharpin and A20 in complex I associated with TNFR1 upon TNFα stimulation. Ubiquitination of RIPK1 by Parkin increases the activation of NF-κB and mitogen-activated protein kinases (MAPKs) by promoting the phosphorylation of inhibitor of kappa B kinase (IKK)α/β and IκBα and nuclear translocation of p65. Thus, we conclude that Parkin modulates the K63 ubiquitination status of RIPK1 to promote the activation of NF-κB and MAPKs.
  • Thumbnail Image
    Publication
    Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression
    (Nature Publishing Group UK, 2018) Zhu, Kezhou; Liang, Wei; Ma, Zaijun; Xu, Daichao; Cao, Shuangyi; Lu, Xiaojuan; Liu, Nan; Shan, Bing; Qian, Lihui; Yuan, Junying
    Necroptosis, a form of regulated necrotic cell death, is mediated by receptor interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). However, the mechanism by which necroptosis promotes inflammation is still unclear. Here we report that the expression of cytokines is robustly upregulated in a cell-autonomous manner during necroptosis induced by tumor necrosis factor alpha (TNFα). We demonstrate that TNFα-induced necroptosis leads to two waves of cytokine production. The first wave, more transient and weaker than the second, is in response to TNFα alone; whereas the second wave depends upon the necroptotic signaling. We show that necroptosis promotes the transcription of TNFα-target genes in a cell-intrinsic manner. The activation of both NF-κB and p38 by the necroptotic machinery, RIPK1, RIPK3, and MLKL, is involved in mediating the robust induction of cytokine expression in the second wave. In contrast, necroptosis induced by direct oligomerization of MLKL promotes cytokine production at much lower levels than that of necroptosis induced with TNFα. Thus, we conclude that TNFα-induced necroptosis signaling events mediated by RIPK1 and RIPK3 activation, in addition to the MLKL oligomerization, promotes the expression of cytokines involving multiple intracellular signaling mechanisms including NF-κB pathway and p38. These findings reveal that the necroptotic cell death machinery mounts an immune response by promoting cell-autonomous production of cytokines. Our study provides insights into the mechanism by which necroptosis promotes inflammation in human diseases.
  • Thumbnail Image
    Publication
    Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death
    (Nature Publishing Group UK, 2018) Ouchida, Amanda Tomie; Li, Yingbo; Geng, Jiefei; Najafov, Ayaz; Ofengeim, Dimitry; Sun, Xiaoxiao; Yu, Qiang; Yuan, Junying
    Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
  • Thumbnail Image
    Publication
    Live imaging and single-cell analysis reveal differential dynamics of autophagy and apoptosis
    (Landes Bioscience, 2013) Xu, Yangqing; Yuan, Junying; Lipinski, Marta M.
    Autophagy is induced by many cytotoxic stimuli but it is often unclear whether, under specific conditions, autophagy plays a prosurvival or a prodeath role. To answer this critical question we developed a novel methodology that employs automated live microscopy and image analysis to measure autophagy and apoptosis simultaneously in single cells. We used this approach to perform a systems-level analysis of pathway dynamics for both autophagy and apoptosis. We found that induction of autophagy in response to different stimuli is uniformly unimodal; in contrast, cells induce apoptosis in an all-or-none bimodal fashion. By tracking the fate of single cells we found that autophagy precedes apoptosis, and that within the same population apoptosis is delayed in cells that mount a stronger autophagy response. Inhibition of autophagy by knocking down ATG5 promoted apoptosis, thus confirming that autophagy plays a protective role. We anticipate that our single-cell approach will be a powerful tool for gaining a quantitative understanding of the complex regulation of autophagy, its influence on cell fate decisions and its relationship with other cellular pathways.
  • Thumbnail Image
    Publication
    Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death
    (The Rockefeller University Press, 2015) Xia, Hong-guang; Najafov, Ayaz; Geng, Jiefei; Galan-Acosta, Lorena; Han, Xuemei; Guo, Yuan; Shan, Bing; Zhang, Yaoyang; Norberg, Erik; Zhang, Tao; Pan, Lifeng; Liu, Junli; Coloff, Jonathan L.; Ofengeim, Dimitry; Zhu, Hong; Wu, Kejia; Cai, Yu; Yates, John R.; Zhu, Zhengjiang; Yuan, Junying; Vakifahmetoglu-Norberg, Helin
    Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non–acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death. Importantly, our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. We reveal a new mechanism by which excessive activation of CMA may be exploited pharmacologically to eliminate cancer cells by inhibiting both FLT3 and autophagy. Our study delineates a novel pharmacological strategy to promote the degradation of HK2 in cancer cells.
  • Thumbnail Image
    Publication
    G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L
    (eLife Sciences Publications, Ltd, 2015) Zhang, Tao; Dong, Kangyun; Liang, Wei; Xu, Daichao; Xia, Hongguang; Geng, Jiefei; Najafov, Ayaz; Liu, Min; Li, Yanxia; Han, Xiaoran; Xiao, Juan; Jin, Zhenzhen; Peng, Ting; Gao, Yang; Cai, Yu; Qi, Chunting; Zhang, Qing; Sun, Anyang; Lipinski, Marta; Zhu, Hong; Xiong, Yue; Pandolfi, Pier Paolo; Li, He; Yu, Qiang; Yuan, Junying
    Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases. DOI: http://dx.doi.org/10.7554/eLife.06734.001