Directing Immunity to Engulfed Cargo
- Jennifer A. Martinez, Ph.D.
Principal Investigator, Inflammation and Autoimmunity
- Tel 984-287-4089
- P.O. Box 12233Mail Drop D2-01Durham, N.C. 27709
Jennifer Martinez, Ph.D. heads the Inflammation and Autoimmunity Group, and holds a secondary appointment in the NIEHS Signal Transduction Laboratory. The Inflammation and Autoimmunity Group investigates the mechanisms by which cargo from the extracellular environment, including pathogens, allergens, and dying cells, is processed by immune cells and how these events influence their pursuant immune response.
Autophagy is an evolutionarily-conserved catabolic pathway designed to preserve a cell’s biosynthetic and energetic function by facilitating the degradation and processing of intracellular contents during times of stress or starvation. Defects in autophagic machinery have been linked with aberrant host defense, inflammatory disease, and age-related disorders. While initial interpretation implicates autophagy in these pathological conditions, recent work demonstrates that a form of non-canonical autophagy, LC3-associated phagocytosis (LAP), is a critical regulator of immunotolerance and a process functionally and molecularly distinct from traditional autophagy. LAP exists at the intersection of the two conserved pathways of autophagy and phagocytosis, wherein the crosstalk between engulfment and processing ultimately shapes the immune response. LAP therefore marries the concepts of phagocytosis and autophagy in a fundamentally new way in which to think about the impact of the autophagy machinery on innate host defense and normal homeostasis. Identification of the LAP-specific gene, Rubicon, and our subsequent generation of the Rubicon-/- mouse as a model of LAP-deficiency (but intact autophagy) allows us to explore the significance of LAP in physiological and pathological settings, though further work is needed to delineate the molecular mechanisms that govern LAP, as well as the molecular mechanisms by which LAP governs inflammation.
This is an emerging field in immunology, and our ability to discriminate between the two processes will have broad applications in tumorigenesis, autoimmunity, and infectious disease. As inhibition of traditional autophagy could be more harmful than beneficial, selective manipulation of LAP could prove to be a tool for immunomodulation. Therefore, it is imperative that the molecular mechanisms that distinguish traditional autophagy and LAP are differentiated, as well as the physiological scenarios in which each is required. In addition to elucidating the mechanisms by which LAP occurs, our long terms goals are to explore the physiological and pathological roles that LAP plays in innate immune function, adaptive immune cell assistance, cellular metabolism, and inflammation.
Relevance to NIEHS Mission
Exposure to environmental stresses can induce profound cellular damage, often resulting in cell death. As the defective clearance of cellular corpses contributes to inflammation and the etiology of numerous autoimmune disorders, our hope is that this work will uncover novel approaches for treating disease. By expanding our understanding how our immune system handles stress and damage, this work will provide valuable insight into the crosstalk between environmental cues and immune homeostasis. In addition, we will actively explore the ability of allergens and pathogens to engage non-canonical autophagy, with the goal of providing insight into the development of new, more effective therapies.
Major Areas of Research:
- Investigating the molecular mechanisms governing the initiation and maintenance of LAP
- Determining how the molecular mechanisms of LC3-associated phagocytosis regulate other cellular processes, such as innate immunity, antigen presentation, and cellular metabolism
- Exploring the role of LAP, as opposed to canonical autophagy, in regulating inflammation and autoimmune disorders
- Identifying LAP-specific infectious pathogens and LAP’s role in controlling these infections
- Studying the impact of mitophagy deficiency and accumulation of damaged mitochondria on disease pathogenesis
- Using biochemical and molecular techniques, such immunoprecipitation and siRNA, to delineate the molecular mechanisms that couple receptor-mediated stimulus sensing to recruitment of the autophagic machinery
- Exploring the mechanisms by which LAP controls lipid/cholesterol sensing and shapes the metabolic profile of the phagocyte
- Investigating the role of LAP in other phagocytic cells, such as dendritic cells, B cells, and tissue-specific phagocytes
- Characterizing the Rubicon-/- mouse, where LAP is defective, but canonical autophagy is intact, in models of autoimmunity and infection
- Daniels BP, Snyder AG, Olsen TM, Orozco S, Oguin TH, 3rd, Tait SW, Martinez J, Gale, M, Jr, Loo, YM, and Oberst A. RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation. Cell. 2017;169(2):301-13 e11. [Abstract]
- Feeley, EM, Pilla-Moffett DM, Zwack EE, Piro AS, Finethy R, Kolb JP, Martinez J, Brodsky IE, and Coers J. Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems. PNAS 2017 doi: 10.1073/pnas.1615771114. [Abstract]
- Martinez J, Cunha LD, Park S, Yang M, Lu Q, Orchard R, Li Q-Z, Yan M, Janke L, Guy C, Linkermann A, Virgin HW, and Green DR. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 2016 May 5;533(7601):115-9. [Abstract]
- Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, Machiah DK, Lawson B, Hakimpour P, Wang YC, Li S, Sharma P, Kaufman RJ, Martinez J, Pulendran B. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 2016 531(7595):523-527. [Abstract]
- Liu L*, Lu Y*, Martinez J*, Wang T, Wang J, Yang M, Liu G, Green DR, and Wang R. Pro-inflammatory stimulation suppresses proliferation and shifts the regulation of macrophage metabolism from a Myc-dependent to a HIF1α-dependent manner. PNAS. 2016 Feb 9;113(6):1564-9. *co-first authorship [Abstract]
- Martinez J, Subbarao MRK, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Tan H, Peng J, Kanneganti TD, Virgin HW, and Green DR. Molecular characterization of LC3-associated phagocytosis (LAP) reveals distinct roles for Rubicon, NOX2, and autophagy proteins. Nature Cell Biology. 2015 Jul;17(7):893-906. [Abstract]
- Kim J-Y*, Zhao H*, Martinez J, Doggett T, Kolesnikov A, Tang P, Ablonczy Z, Chan C, Zhou Z, Green D, Ferguson T. Non-canonical autophagy promotes the visual cycle. Cell 154(2): 365-376, 2013. *co-first authorship [Abstract]
- Henault J*, Martinez J*, Riggs JM, Tian J, Mehta P, Clarke L, Sasai M, Latz E, Brinkmann MM, Coyle AJ, Kolbeck R, Green DR, Sanjuan MA. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37(6): 986-997, 2012. *co-first authorship [Abstract]
- Martinez J, Almendinger J, Oberst A, Ness R, Dillon C, Fitzgerald P, Hengartner M, and Green D. Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells. PNAS. 108(42): 17396-401, 2011. [Abstract]
Martinez earned her B.S. in Cellular and Molecular Biology from Tulane University in 2001 and her Ph.D. in immunology from Duke University in 2010. She began her work on the autophagy machinery and its role in inflammation and host defense as a postdoctoral fellow in the laboratory of Douglas R. Green, Ph.D., at the St. Jude Children’s Research Hospital, Memphis, Tennessee. After completing her fellowship, she joined the NIEHS Immunity, Inflammation, and Disease Laboratory as a Tenure-track Investigator in 2015.