Jennifer A. Martinez
Inflammation & Autoimmunity
Institut Pasteur de Bangui
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.
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
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.
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