publications

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

06/18/2018 ○ Nature - Sci Rep. Fulltext
Handong Zheng1, Dandan Wu2,3, Xiang Wu1,4, Xing Zhang2, Qin Zhou1, Yan Luo2, Xin Yang2, Cameron J. Chock1, Meilian Liu5,6 & Xuexian O. Yang7,8
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.
5Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA. meilianliu@salud.unm.edu.
6Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA. meilianliu@salud.unm.edu.
7Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA. xyang@salud.unm.edu.
8Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA. xyang@salud.unm.edu.

Allergic asthma and obesity are major public health problems in the world. Recent Meta-analysis studies implicated a positive relationship between serum leptin, which is elevated in obese individuals, and the risk of asthma. However, it is not well understood how obesity-associated elevation of leptin increases the risk of asthma. In the current study, we have found that leptin induces the unfolded protein response factor XBP1s in an mTOR- and MAPK-dependent manner in pro-allergic TH2 cells; in vivo, mice fed with high fat diet had increased serum leptin as observed in human obese population and exacerbated asthmatic symptoms, associated with increased XBP1s expression in splenic CD4+ T cells. XBP1s is required for leptin-mediated pro-allergic TH2 cell survival and cytokine production. Our results reveal a previously unappreciated insight that obesity-associated hyperleptinemia contributes to enhanced pro-allergic lymphocyte responses through induction of XBP1s, leading to exacerbation of allergic asthma.

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

3/23/2018 ○ Semin Cell Dev Biol Fulltext
Claude-Taupin A1, Bissa B1, Jia J1, Gu Y1, Deretic V2
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.
2Autophagy 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. Electronic address: vderetic@salud.unm.edu.

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.

Galectins Control mTOR in Response to Endomembrane Damage

03/05/2018 ○ Molecular Cell Fulltext
Jingyue Jia1,2, Yakubu Princely Abudu3, Aurore Claude-Taupin1,2, Yuexi Gu1,2,Suresh Kumar1,2, Seong Won Choi1,2, Ryan Peters1,2, Michal H. Mudd1,2, Lee Allers1,2, Michelle Salemi4, Brett Phinney4, Terje Johansen3,Vojo Deretic1,2,5
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
2Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA
3Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
4Proteomics 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.

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

2/2/2018 ○ J Cell Biol Fulltext
Kumar S1,2, Jain A3, Farzam F4, Jia J1,2, Gu Y1,2, Choi SW1,2, Mudd MH1,2, Claude-Taupin A1,2, Wester MJ5, Lidke KA4, Rusten TE3, Deretic V6,2
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.unm.edu.

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.

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

02/01/2018 ○ Sci Dir. Fulltext
Castillo EF1, Zheng H2, Yang XO3.
1Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA. Electronic address: ECastillo@salud.unm.edu.
2Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.
3Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA. Electronic address: xyang@salud.unm.edu.

Allergic asthma, a chronic respiratory disease, is a leading worldwide health problem, which inflames and constricts the airways, leading to breathing difficulty. Many studies have focused on the pathogenesis contributed by the adaptive immune system, including CD4+ T lymphocytes in delayed type hypersensitivity and B cell-produced IgE in anaphylaxis. More recently, a focus on the airway mucosal barrier and the innate immune system has highlighted, in coordination with T and B cells, to initiate and establish disease. This review highlights the impacts of epithelial-derived cytokines and innate immune cells on allergic airway reactions.

Autophagy and inflammation: A special review issue

1/29/2018 ○ Autophagy Fulltext
Deretic V1,2, Klionsky DJ3.
1Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM USA
2Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence , University of New Mexico Health Sciences Center , Albuquerque , NM USA
3Life 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 balances inflammation in innate immunity

1/1/2018 ○ Autophagy Fulltext
Deretic V1,2, Levine B3,4,5
1Autophagy, Inflammation and Metabolism in Disease (AIM) Center of Biomedical Research Excellence , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
2Department of Molecular Genetics and Microbiology , University of New Mexico Health Sciences Center , Albuquerque , NM , USA.
3Center for Autophagy Research, Department of Internal Medicine , University of Texas Southwestern Medical Center , Dallas , TX , USA.
4Department of Microbiology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
5Howard 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.

Autophagy's secret life: secretion instead of degradation

12/12/2017 ○ Essays Biochem Fulltext
Claude-Taupin A1,2, Jia J1,2, Mudd M1,2, Deretic V3,2.
1Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, U.S.A.
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.S.A.
3Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, U.S.A. vderetic@salud.unm.edu.

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

12/10/2017 ○ Adv Exp Med Biol Fulltext
Sharma G1, Prossnitz ER2,3
1Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. gsharma@salud.unm.edu.
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. eprossnitz@salud.unm.edu.
3University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. eprossnitz@salud.unm.edu.

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.