publications

Adipose mTORC1 Suppresses Prostaglandin Signaling and Beige Adipogenesis via the CRTC2-COX-2 Pathway.

9/21/2018 ○ Cell Rep Fulltext
Zhang, Xing1, Luo, Yan2, Wang, Chunqing3, Ding, Xiaofeng1, Yang, Xin3, Wu, Dandan3, Silva, Floyd3, Yang, Zijiang3, Zhou, Qin3, Wang, Lu3, Wang, Xiaoqing4, Zhou, Jianlin5, Boyd, Nathan6, Spafford, Michael6, Burge, Mark7, Yang, Xuexian O8, Liu, Meilian9
1Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan, China
2Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
3Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
4Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
5Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, Hunan, China
6Department of Surgery, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
7Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
8Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
9Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

Beige adipocytes are present in white adipose tissue (WAT) and have thermogenic capacity to orchestrate substantial energy metabolism and counteract obesity. However, adipocyte-derived signals that act on progenitor cells to control beige adipogenesis remain poorly defined. Here, we show that adipose-specific depletion of Raptor, a key component of mTORC1, promoted beige adipogenesis through prostaglandins (PGs) synthesized by cyclooxygenase-2 (COX-2). Moreover, Raptor-deficient mice were resistant to diet-induced obesity and COX-2 downregulation. Mechanistically, mTORC1 suppressed COX-2 by phosphorylation of CREB-regulated transcription coactivator 2 (CRTC2) and subsequent dissociation of CREB to cox-2 promoter in adipocytes. PG treatment stimulated PKA and promoted differentiation of progenitor cells to beige adipocytes in culture. Ultimately, we show that pharmacological inhibition or suppression of COX-2 attenuated mTORC1 inhibition-induced thermogenic gene expression in inguinal WAT in vivo and in vitro. Our study identifies adipocyte-derived PGs as key regulators of white adipocyte browning, which occurs through mTORC1 and CRTC2.

Leptin Promotes Allergic Airway Inflammation through Targeting the Unfolded Protein Response Pathway.

6/13/2018 ○ Sci Rep Fulltext
Zheng, Handong1, Wu, Dandan2,3, Wu, Xiang1,4, Zhang, Xing2, Zhou, Qin1, Luo, Yan2, Yang, Xin2, Chock, Cameron J1, Liu, Meilian2,5, Yang, Xuexian O1,5
1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
2Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
3College of Agronomy, Hunan Agricultural University, Changsha, Hunan, 410128, China
4Department of Parasitology, School of Basic Medical Sciences, Xiangya School of Medicine, Central South University, Changsha, China
5Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

Galectins Control mTOR in Response to Endomembrane Damage.

4/7/2018 ○ Mol. Cell Fulltext
Jia, Jingyue1, Abudu, Yakubu Princely2, Claude-Taupin, Aurore1, Gu, Yuexi1, Kumar, Suresh1, Choi, Seong Won1, Peters, Ryan1, Mudd, Michal H1, Allers, Lee1, Salemi, Michelle3, Phinney, Brett3, Johansen, Terje2, Deretic, Vojo1
1Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA; Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
2Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø-The Arctic University of Norway, 9037 Tromsø, Norway
3Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, CA 95616, USA

The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism-independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of galectin-8 (Gal8) with the mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery, whereas galectin-9 activates AMPK in response to lysosomal injury. Both systems converge upon downstream effectors including autophagy and defense against Mycobacterium tuberculosis. Thus, a novel galectin-based signal-transduction system, termed here GALTOR, intersects with the known regulators of mTOR on the lysosome and controls them in response to lysosomal damage. VIDEO ABSTRACT.

Role of autophagy in IL-1β export and release from cells.

3/28/2018 ○ Semin. Cell Dev. Biol. Fulltext
Claude-Taupin, Aurore1, Bissa, Bhawana1, Jia, Jingyue1, Gu, Yuexi1, Deretic, Vojo1
1Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 USA; Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131 USA

The autophagy pathway known also as macroautophagy (herein referred to as autophagy) is characterized by the formation of double-membrane organelles that capture cytosolic material. Based on pathway termination alternatives, autophagy has been divided into degradative and secretory. During degradative autophagy, autophagosomes typically fuse with lysosomes upon which the sequestered material is degraded. During secretory autophagy, instead of degradation the sequestered cargo is subjected to active secretion or passive release. In this review, we focus on the mechanisms of secretion/passive release of the potent pro-inflammatory cytokine IL-1β, as a prototypical leaderless cytosolic protein cargo studied in the context of secretory autophagy.

Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins.

2/9/2018 ○ J. Cell Biol. Fulltext
Kumar, Suresh1,2, Jain, Ashish3, Farzam, Farzin4, Jia, Jingyue1,2, Gu, Yuexi1,2, Choi, Seong Won1,2, Mudd, Michal H1,2, Claude-Taupin, Aurore1,2, Wester, Michael J5, Lidke, Keith A4, Rusten, Tor-Erik3, Deretic, Vojo6,2
1Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
2Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM
3Department of Molecular Cell Biology, Centre for Cancer Biomedicine, University of Oslo and Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
4Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM
5Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM
6Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM vderetic@salud

Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM. Both IRGM and Stx17 directly interact with mammalian Atg8 proteins, thus being guided to autophagosomes. We also show that Stx17 is significant in defense against infectious agents and that Stx17-IRGM interaction is targeted by an HIV virulence factor Nef.

Autophagy and inflammation: A special review issue.

1/7/2018 ○ Autophagy Fulltext
Deretic, Vojo1,2, Klionsky, Daniel J3
1a Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM USA
2b Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence , University of New Mexico Health Sciences Center , Albuquerque , NM USA
3c Life Sciences Institute, University of Michigan , Ann Arbor , MI USA

Macroautophagy/autophagy is a fundamental intracellular homeostatic process that is of interest both for its basic biology and for its effect on human physiology in a wide spectrum of conditions and diseases. Autophagy was first appreciated primarily as a metabolic and cytoplasmic quality control process, but in the past decade its role in immunity has been steadily growing. The connections between these aspects beckon explorations of the network and connections that exist between metabolism, quality control, and inflammation and immunity processes, which are so key to many human diseases including neurodegeneration, obesity and diabetes, chronic inflammatory conditions, cancer, infection, and aging. The purpose of this issue is to stimulate further the burgeoning studies of the intersections between autophagy and inflammation, and the inevitable overlaps with metabolic and quality control functions of autophagy.

Autophagy's secret life: secretion instead of degradation.

12/14/2017 ○ Essays Biochem. Fulltext
Claude-Taupin, Aurore1,2, Jia, Jingyue1,2, Mudd, Michal1,2, Deretic, Vojo1,2
1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, U
2Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, U

Autophagy is conventionally described as a degradative, catabolic pathway and a tributary to the lysosomal system where the cytoplasmic material sequestered by autophagosomes gets degraded. However, autophagosomes or autophagosome-related organelles do not always follow this route. It has recently come to light that autophagy can terminate in cytosolic protein secretion or release of sequestered material from the cells, rather than in their degradation. In this review, we address this relatively new but growing aspect of autophagy as a complex pathway, which is far more versatile than originally anticipated.

G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis.

12/11/2017 ○ Adv. Exp. Med. Biol. Fulltext
Sharma, Geetanjali1, Prossnitz, Eric R2,3
1Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
2Division of Molecular Medicine, Department of Internal Medicine, and Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
3University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

Obesity and metabolic syndrome display disparate prevalence and regulation between males and females. Human, as well as rodent, females with regular menstrual/estrous cycles exhibit protection from weight gain and associated chronic diseases. These beneficial effects are predominantly attributed to the female hormone estrogen, specifically 17β-estradiol (E2). E2 exerts its actions via multiple receptors, nuclear and extranuclear estrogen receptor (ER) α and ERβ, and the G-protein-coupled estrogen receptor (GPER, previously termed GPR30). The roles of GPER in metabolic homeostasis are beginning to emerge but are complex and remain unclear. The discovery of GPER-selective pharmacological agents (agonists and antagonists) and the availability of GPER knockout mice have significantly enhanced our understanding of the functions of GPER in normal physiology and disease. GPER action manifests pleiotropic effects in metabolically active tissues such as the pancreas, adipose, liver, and skeletal muscle. Cellular and animal studies have established that GPER is involved in the regulation of body weight, feeding behavior, inflammation, as well as glucose and lipid homeostasis. GPER deficiency leads to increased adiposity, insulin resistance, and metabolic dysfunction in mice. In contrast, pharmacologic stimulation of GPER in vivo limits weight gain and improves metabolic output, revealing a promising novel therapeutic potential for the treatment of obesity and diabetes.

Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation.

11/25/2017 ○ Cytokine Growth Factor Rev. Fulltext
Castillo, Eliseo F1, Zheng, Handong1, Yang, Xuexian O1
1Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA

Autophagy balances inflammation in innate immunity.

11/23/2017 ○ Autophagy Fulltext
Deretic, Vojo1,2, Levine, Beth3,4,5
1a Autophagy, Inflammation and Metabolism in Disease (AIM) Center of Biomedical Research Excellence , University of New Mexico Health Sciences Center , Albuquerque , NM , USA
2b Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA
3c Center for Autophagy Research, Department of Internal Medicine , University of Texas Southwestern Medical Center , Dallas , TX , USA
4d Department of Microbiology , University of Texas Southwestern Medical Center , Dallas , TX , USA
5e Howard Hughes Medical Institute , University of Texas Southwestern Medical Center , Dallas , TX , USA

Macroautophagy/autophagy is a homeostatic process with multiple effects on immunity. One of the pivotal contributions of autophagy in immunity is the cell autonomous control of inflammation. This property leads to systemic consequences and thereby influences the development of innate and adaptive immunity, which promotes or suppresses pathology in various disease contexts. In this review we focus on the intersections between autophagy and inflammasome activation, autophagy and interferons, and autophagy and inflammation in association with infection.