All publications from Yuan Lab (Google Scholar link):
- Pharmacologic agents targeting autophagy. Vakifahmetoglu-Norberg H, Xia HG, Yuan J. J Clin Invest. 2015 Jan;125(1):5-13. doi: 10.1172/JCI73937.
- Activation of necroptosis in multiple sclerosis. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Berlink Lima J, Qi C, Yu Q, Trapp B, Yuan J. Cell Rep. 2015 Mar 24;10(11):1836-49.
- Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. Xia HG, Najafov A, Geng J, Galan-Acosta L, Han X, Guo Y, Shan B, Zhang Y, Norberg E, Zhang T, Pan L, Liu J, Coloff JL, Ofengeim D, Zhu H, Wu K, Cai Y, Yates JR, Zhu Z, Yuan J, Vakifahmetoglu-Norberg H. J Cell Biol. 2015 Aug 31;210(5):705-16.
- G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L. Zhang T, Dong K, Liang W, Xu D, Xia H, Geng J, Najafov A, Liu M, Li Y, Han X, Xiao J, Jin Z, Peng T, Gao Y, Cai Y, Qi C, Zhang Q, Sun A, Lipinski M, Zhu H, Xiong Y, Pandolfi PP, Li H, Yu Q, Yuan J. Elife. 2015 Mar 30;4:e06734.
- FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation. Xiao J, Zhang T, Xu D, Wang H, Cai Y, Jin T, Liu M, Jin M, Wu K, Yuan J. Genes Dev2015 Jan 15;29(2):184-96.
- Modification of BECN1 by ISG15 plays a crucial role in autophagy regulation by type I IFN/interferon. Xu D, Zhang T, Xiao J, Zhu K, Wei R, Wu Z, Meng H, Li Y, Yuan J. Autophagy 2015 Apr 3;11(4):617-28.
- Necroptosis in health and diseases. Z hou W, Yuan J. Semin Cell Dev Biol. 2014 Nov;35:14-23.
- SnapShot: Necroptosis. Zhou W, Yuan J. Cell. 2014 Jul 17;158(2):464-464.e1.
- Caspase-11 controls interleukin-1ß release through degradation of TRPC1. Py BF, Jin M, Desai BN, Penumaka A, Zhu H, Kober M, Dietrich A, Lipinski MM, Henry T, Clapham DE, Yuan J. Cell Rep. 2014 Mar 27;6(6):1122-8.
- Control of life-or-death decisions by RIP1 kinase. Christofferson DE, Li Y, Yuan J. Annu Rev Physiol. 2014;76:129-50.
- A degradative detour for mutant TP53. Vakifahmetoglu-Norberg H, Yuan J. Autophagy. 2013 Dec;9(12):2158-60.
- Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Ofengeim D, Yuan J. Nat Rev Mol Cell Biol. 2013 Nov;14(11):727-36.
- Chaperone-mediated autophagy degrades mutant p53. Vakifahmetoglu-Norberg H, Kim M, Xia HG, Iwanicki MP, Ofengeim D, Coloff JL, Pan L, Ince TA, Kroemer G, Brugge JS, Yuan J. Genes Dev. 2013 Aug 1;27(15):1718-30.
- Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity. Py BF, Gonzalez SF, Long K, Kim MS, Kim YA, Zhu H, Yao J, Degauque N, Villet R, Ymele-Leki P, Gadjeva M, Pier GB, Carroll MC, Yuan J. Immunity. 2013 May 23;38(5):1063-72.
- Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. Mol Cell. 2013 Jan 24;49(2):331-8.
- A novel role for RIP1 kinase in mediating TNFa production. Christofferson DE, Li Y, Hitomi J, Zhou W, Upperman C, Zhu H, Gerber SA, Gygi S, Yuan J. Cell Death Dis. 2012 Jun 14;3:e320.
- Integration of apoptosis and metabolism. Yi CH, Vakifahmetoglu-Norberg H, Yuan J. Cold Spring Harb Symp Quant Biol. 2011;76:375-87.
- Alternative cell death mechanisms in development and beyond. Yuan J, Kroemer G. Genes Dev. 2010 Dec 1;24(23):2592-602.
- Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14164-9.
- A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Lipinski MM, Hoffman G, Ng A, Zhou W, Py BF, Hsu E, Liu X, Eisenberg J, Liu J, Blenis J, Xavier RJ, Yuan J. Dev Cell. 2010 Jun 15;18(6):1041-52.
- Negative regulation of Vps34 by Cdk mediated phosphorylation. Furuya T, Kim M, Lipinski M, Li J, Kim D, Lu T, Shen Y, Rameh L, Yankner B, Tsai LH, Yuan J. Mol Cell. 2010 May 28;38(4):500-11.
- Role of protein misfolding in DFNA9 hearing loss. Yao J, Py BF, Zhu H, Bao J, Yuan J. J Biol Chem. 2010 May 14;285(20):14909-19.
- Necroptosis as an alternative form of programmed cell death. Christofferson DE, Yuan J. Curr Opin Cell Biol. 2010 Apr;22(2):263-8.
- Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Yuan J. Apoptosis. 2009 Apr;14(4):469-77.
- A critical role of eEF-2K in mediating autophagy in response to multiple cellular stresses. Py BF, Boyce M, Yuan J. Autophagy. 2009 Apr;5(3):393-6.
- The Jekyll and Hyde functions of caspases. Yi CH, Yuan J. Dev Cell. 2009 Jan;16(1):21-34.
- Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J. Cell. 2008 Dec 26;135(7):1311-23.
- Caspases in apoptosis and beyond. Li J, Yuan J. Oncogene. 2008 Oct 20;27(48):6194-206.
- Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Zhu J, Blenis J, Yuan J. Proc Natl Acad Sci U S A. 2008 May 6;105(18):6584-9.
- Flightless-I regulates proinflammatory caspases by selectively modulating intracellular localization and caspase activity. Li J, Yin HL, Yuan J. J Cell Biol. 2008 Apr 21;181(2):321-33.
- A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death. Boyce M, Py BF, Ryazanov AG, Minden JS, Long K, Ma D, Yuan J. Cell Death Differ. 2008 Mar;15(3):589-99.
- Inducing autophagy harmlessly. Yuan J. Autophagy. 2008 Feb;4(2):249-50.
- Identification of RIP1 kinase as a specific cellular target of necrostatins. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Nat Chem Biol. 2008 May;4(5):313-21.
- Expansion and evolution of cell death programmes. Degterev A, Yuan J. Nat Rev Mol Cell Biol. 2008 May;9(5):378-90.
Selected Publications and Highlights
1) Molecular mechanisms of apoptosis.
Miura, M., Zhu, H., Rotello, R., Hartwieg, E.A., and Yuan, J. (1993). Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75, 653-660.
- Highlight: This was the first demonstration of a mammalian caspase, caspase-1 (termed IL-1 beta-converting enzyme at the time), in mediating apoptosis and the ability of Bcl-2 to suppress apoptosis induced by overexpression of caspase-1. This study provided direct evidence for the functional role of mammalian caspases as homologues of C. elegans Ced-3 and a direct link between an anti-apoptotic member of Bcl-2 family and a caspase in regulating apoptosis of mammalian cells.
- Highlight: This was the first demonstration of the role of neuronal caspases in mediating trophic factor deprivation induced apoptosis and provided the first insight into the molecular mechanism that executes neuronal apoptosis.
- Highlight: This study demonstrated the critical role of BID, after its cleavage by caspase-8, as a signal transducer in mediating mitochondrial damage in response to the activation of death receptors.
- Highlight: This study demonstrated the role of caspase-11 in mediating caspase-1 activation and IL1-beta processing after LPS stimulation and established caspase-11 as an upstream regulator of caspase-1.
Yi, C.H., Pan, H., Seebacher, J., Jang, I.H., Hyberts, S.G., Heffron, G.J., Vander Heiden, M.G., Yang, R., Li, F., Locasale, J.W., et al. (2011). Metabolic regulation of protein N-alpha-acetylation by Bcl-xL promotes cell survival. Cell 146, 607-620.
- Highlight: This study established an in vitro assay using subtiligase to measure the levels of protein N-terminal acetylation and demonstrated that N-alpha-acetylation is sensitive to metabolic regulation. Furthermore, this study demonstrated that Bcl-xL expression can control the levels of protein N-alpha-acetylation by regulating the levels of acetyl-CoA which provides a Bax/Bak independent mechanism to regulate apoptotic sensitivity.
2) The roles and mechanisms of apoptosis in neurodegeneration.
Friedlander, R.M., Gagliardini, V., Hara, H., Fink, K.B., Li, W., MacDonald, G., Fishman, M.C., Greenberg, A.H., Moskowitz, M.A., and Yuan, J. (1997). Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 185, 933-940.
- Highlight: This study provides the first in vivo evidence for the role of caspases in mediating acute neurological damage.
- Highlight: This study demonstrated the ability of oligomerized expanded polyglutamine repeats to mediate the activation of caspase-8 and implicated the role of caspases in Huntington’s disease.
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A., and Yuan, J. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103.
- Highlight: This study demonstrated the role of caspase-12 as a mediator of ER stress induced apoptosis and in mediating Abeta induced neuronal cell death.
3) Necroptosis, a regulated necrotic cell death pathway:
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., and Yuan, J. (2005). Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1, 112-119.
- Highlight: Using a cell-based assay that undergoes caspase-independent cell death, Degterev et al. isolated a small molecule inhibitor, termed necrostatin-1 (Nec-1), that can potently inhibit this form of cell death. Degterev et al. found that this form of caspase-independent cell death is distinct from any known cell death pathways and named this pathway "necroptosis".
Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I.L., Korkina, O., Teng, X., Abbott, D., Cuny, G.D., Yuan, C., Wagner, G., Hedrick, S.M.,Gerber, S.A., Lugovskoy A & Yuan, J. (2008). Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4, 313-321.
- Highlight: This study identified RIP1 kinase as the target of necrostatin-1, necrostatin-3 and necrostatin-4 and necrostatin-5 and established the critical role of RIP1 kinase in mediating necroptosis.
Hitomi, J., Christofferson, D.E., Ng, A., Yao, J., Degterev, A., Xavier, R.J., and Yuan, J. (2008). Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135,1311-1323.
- Highlight: Hitomi et al. screened siRNA library targeting 16873 genes in the human genome for genes involved in mediating necroptosis and identified a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. This study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.
4) Regulation of autophagy in cancers and neurodegeneration.
Furuya, T., Kim, M., Lipinski, M., Li, J., Kim, D., Lu, T., Shen, Y., Rameh, L., Yankner, B., Tsai, L.H. & Yuan, J. (2010). Negative regulation of Vps34 by Cdk mediated phosphorylation. Mol Cell 38, 500-511.
- Highlight: This study explored the control of autophagy and class III PI3 kinase during mitosis and demonstrated that phosphorylation of Vps34 by Cdks negatively regulates its lipid kinase activity. Inhibition of Vps34 during mitosis provides a mechanism for autophagy inhibition during mitosis and also when Cdk5 is activated during neurodegeneration.
Lipinski, M.M., Hoffman, G., Ng, A., Zhou, W., Py, B.F., Hsu, E., Liu, X., Eisenberg, J., Liu, J., Blenis, J., Xavier, R.J. & Yuan, J. (2010a). A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Dev Cell 18, 1041-1052.
- Highlight: This study conducted a genome-wide siRNA screen for genes that regulate autophagy under normal nutrient conditions and demonstrated that the activation of type III PI3 kinase, but not inhibition of mTORC1, is the common regulator of autophagy under normal nutritional condition.
Lipinski, M.M., Zheng, B., Lu, T., Yan, Z., Py, B.F., Ng, A., Xavier, R.J., Li, C., Yankner, B.A., Scherzer, C.R. & Yuan, J. (2010b). Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A 107, 14164-14169.
- Highlight: This study investigated the mechanism that regulate autophagy during aging and Alzheimer’s disease and demonstrated that autophagy is transcriptionally down-regulated during normal aging in the human brain while transcriptionally up-regulation of autophagy in the brains of AD patients.
Liu, J., Xia, H., Kim, M., Xu, L., Li, Y., Zhang, L., Cai, Y., Norberg, H.V., Zhang, T., Furuya, T., Jin, M., Zhu, Z., Wang, H., Yu, J., Hao, Y., Choi, A., Ke, H., Ma, D. & Yuan, J. (2011). Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147, 223-234.
- Highlight: This study identified a potent small molecule inhibitor of autophagy named "spautin-1" that promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13. This study also demonstrated the ability of Beclin1 to control the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. This study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
5) Development of small molecule probes for studying cell death and neurodegeneration.
Degterev, A., Lugovskoy, A., Cardone, M., Mulley, B., Wagner, G., Mitchison, T., and Yuan, J. (2001). Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3, 173-182.
- Highlight: Degterev et al. developed a fluorescence polarization based assay for screening small molecules that can inhibit the binding of pro-apoptotic Bcl-2 family member Bak with anti-apoptotic Bcl-2 family member Bcl-xL. This study characterized the interaction of BH3-mimetic small molecules with Bcl-xL using multiple biophysical methods such as surface-enhanced laser desorption/ionization (SELDI) chip, mass spectrometry and NMR analyses as well as multiple cellular assays to reveal the ability of small molecules in targeting the BH3-binding pocket of Bcl-xL.
Boyce, M., Bryant, K.F., Jousse, C., Long, K., Harding, H.P., Scheuner, D., Kaufman, R.J., Ma, D., Coen, D.M., Ron, D. & Yuan, J. (2005). A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307, 935-939.
- Highlight: Using a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, Boyce et al. identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha) and the ability of salubrinal to block eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. This study provides a proof-in-principle for the feasibility of selective pharmacological targeting of cellular dephosphorylation events.
- Highlight: Using azo-dye Congo red which binds preferentially to beta-sheets containing amyloid fibrils and can inhibit oligomerization of expanded polyglutamine repeats, Sanchez et al. demonstrated the principle that inhibiting oligomerization can promote the clearance of expanded polyglutamine repeats in vivo and in vitro, preserve normal cellular protein synthesis and degradation functions and maintain cell viability.
- Text and Interview by Nicole LeBrasseur. Junying Yuan: Changing avenues without losing focus. Published online 22 October 2007. The Journal of Cell Biology, Vol. 179, No. 2, 174-175
- Brainy Women: At the frontiers of neuroscience. Harvard Magazine (cover article).
Reviews, Chapters, and Editorials
(1) Ellis R, Yuan J, Horvitz HR. Mechanisms and functions of cell death. Ann. Rev. Cell. Biol. 1991; 7:663-698
(2) Yuan, J. Molecular Control of life and death. Cur. Opin. in Cell Biol. 1995; 7:211-214.
(3) Yuan, J. The genes that regulate programmed cell death: from worm to mammal. Proceedings of Princeton Conference. 1995. In: Cerebrovascular Diseases. Nineteenth Princeton Stroke Conference. M. A. Moskowitz and L. R. Caplan (eds). Butterworth-Heinemann, Boston, MA. pp199-218.
(4) Miura M, Yuan J. Mechanisms of programmed cell death in C. elegans and vertebrates. Current Topics in Biology. 1996; Vol 32: pp.139-174.
(5) Yuan, J. Evolutionary conservation of a genetic pathway of programmed cell death. J. Cellu Biochem. 1996; 60:4-11.
(6) Drexler HCA, Yuan J. Control of cell death in the nervous system. In: Apoptosis in Normal Development and Cancer. M. Sluyser, ed. Taylor and Francis, Inc. 1996; pp.277-298.
(7) Yuan J. 1997. Genetic control of cellular suicide. Reprod. Toxicology.11/2-3: p377-384.
(8) Yuan J. Transducing signals of life and death. Curr Opin Cell Biol. 1997; 9: 247-251.
(9) Lustig KD, Stukenberg PT, McGarry TJ, King RW, Cryns VL, Mead PE, Zon LI, Yuan J, and Kirschner MW. Small pool expression screening: a novel strategy for the identification of genes involved in cell cycle control, apoptosis and early development. Meths. of Enz. 1997; 283:83-99
(10) Cryns VL and Yuan J. The cutting edge: ICE/CED-3 proteases in apoptosis and disease. In: Lockshin RA, Zakeri Z, and Tilly L, eds. 1998. Why Cells Die: A Comprehensive Evaluation of Apoptosis and Programmed Cell Death.
(11) Bergeron L, & Yuan J. Sealing one's fate: control of neuronal cell death. Current Opinion in Neurobiology. 1998; 8:55-63.
(12) Cryns VL and Yuan J. Proteases to die for. Gen. & Dev. 1998; 12: 1551-1570.
(13) Friedlander RM and Yuan J. ICE, neuronal apoptosis and neurodegeneration. Cell Death & Diff. 1998; 5:823-831.
(14) Li H & Yuan J. Deciphering the Pathways of Life and Death. Current Opinion in Cell Biology. 1999; 11: 261-266.
(15) Yuan J & Yankner B. Seeds of death: Caspase Cleavage and the Generation of Toxic Protein Fragments in Alzheimer's and Huntington's Diseases. News & Views. Nature Cell Biology. 1999. 1, E44- E45.
(16) Degterev A and Yuan J. A new savior for neurons. News & Views. Nature Neuroscience. 1999. 2, 930-932.
(18) Sanchez I and Yuan J. A convoluted way to die. Neuron. 2001. 29, 563-566.
(19) Degterev A, Boyce M, Yuan J. The channel of death. J Cell Biol. 2001. 155, 695-8.
(20) Welch K, Yuan J. Releasing the nerve cell killers. Nat Med. 2002. 8, 564-5.
(21) Gozani O, Boyce M, Yoo L, Karuman P, Yuan J. Life and death in paradise. Nat Cell Biol. 2002. 4, E159-62.
(22) Yoo LI, Chung DC, Yuan J. LKB1--a master tumour suppressor of the small intestine and beyond. Nat Rev Cancer. 2002. 2, 529-3.
(23) Yuan J and Morgan D. (eds). Cell division, growth and death. Current Opinion in Cell Biology. 2002. Vol. 14. No. 6.
(24) Yuan J, Lipinski M, Degterev A Diversity in the mechanisms of neuronal cell death. Neuron. 2003. 40, 401-13.
(25) Welch K, Yuan J. Alpha-synuclein oligomerization: a role for lipids? Trends Neurosci. 2003. 26, 517-9.
(26) Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene. 2003. 22, 8543-8567.
(27) Boyce M, Degterev A, and Yuan J. Caspases: an ancient cellular sword of Damocles. Cell Death and Differ. 2004. 11. 29-37.
(28) Yuan J and Horvitz HR. A first insight into the molecular mechanisms of apoptosis. Cell. 2004. S116. S53-S56.
(29) Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005. 115, 2679-88.
(31) Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006. Jan 6.
(32) Yuan J. (ed). Special Issue on ER stress. Cell Death Differ. 2006 Jan 6.
(40) Yi CH, Vakifahmetoglu-Norberg H, Yuan J. Integration of Apoptosis and Metabolism. Cold Spring Harb Symp Quant Biol. 2011 Nov 16.