Showing papers by "Vojo Deretic published in 2013"
TL;DR: As discussed in this Review, autophagy has multitiered immunological functions that influence infection, inflammation and immunity.
Abstract: It is increasingly understood that autophagy is an ancient defence mechanism that has become incorporated into numerous immunological pathways. As discussed in this Review, its immunological roles include the elimination of microorganisms, the control of inflammation, the regulation of antigen presentation and lymphocyte homeostasis, and the secretion of immune mediators.
1,549 citations
TL;DR: It is found for the first time that heat shock response controls autophagy thus connecting and coordinating the two extreme ends of the homeostatic systems in the eukaryotic cell.
138 citations
TL;DR: The role of autophagy in secretion is more complex, at least in mammalian cells, than the simplistic view that autophagosomes provide carriers for unconventional secretion of cytosolic proteins.
Abstract: Autophagy (macroautophagy) is often defined as a degradative process and a tributary of the lysosomal pathway. In this context, autophagy carries out cytoplasmic quality control and nutritional functions by removing defunct or disused organelles, particulate targets and invading microbes, and by bulk digestion of the cytoplasm. However, recent studies indicate that autophagy surprisingly affects multiple secretory pathways. Autophagy participates in extracellular delivery of a number of cytosolic proteins that do not enter the conventional secretory pathway via the Golgi apparatus but are instead unconventionally secreted directly from the cytosol. In mammalian cells, a prototypical example of this manifestation of autophagy is the unconventional secretion of a major proinflammatory cytokine, IL-1β. This review examines the concept of secretory autophagy and compares and contrasts the role of autophagy in the secretion of IL-1α and IL-1β. Although IL-1α and IL-1β have closely related extracellular inflammatory functions, they differ in intracellular activation, secretory mechanisms and how they are affected by autophagy. This example indicates that the role of autophagy in secretion is more complex, at least in mammalian cells, than the simplistic view that autophagosomes provide carriers for unconventional secretion of cytosolic proteins.
117 citations
TL;DR: Genome wide association studies indicate a considerable overlap between autophagy, human susceptibility to mycobacterial infections and predisposition loci for inflammatory bowel disease, and recent studies show that Autophagy is an important regulator and effector of IL-1 responses, and that autphagy intersects with type I interferon pathology-modulating responses.
94 citations
TL;DR: A regulatory mechanism that coordinates Golgi–ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide and their regulatory factors is identified, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.
Abstract: Endoplasmic reticulum (ER)-Golgi membrane transport and autophagy are intersecting trafficking pathways that are tightly regulated and crucial for homeostasis, development and disease. Here, we identify UVRAG, a beclin-1-binding autophagic factor, as a phosphatidylinositol-3-phosphate (PtdIns(3)P)-binding protein that depends on PtdIns(3)P for its ER localization. We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity. Intriguingly, autophagy caused the dissociation of UVRAG from the ER tether, which in turn worked in concert with the Bif-1-beclin-1-PI(3)KC3 complex to mobilize Atg9 translocation for autophagosome formation. These findings identify a regulatory mechanism that coordinates Golgi-ER retrograde and autophagy-related vesicular trafficking events through physical and functional interactions between UVRAG, phosphoinositide and their regulatory factors, thereby ensuring spatiotemporal fidelity of membrane trafficking and maintenance of organelle homeostasis.
77 citations
Patent•
15 Oct 2013
TL;DR: In this paper, a method for treating a subject suffering from a Mycobacterium infection by administering to the subject a therapeutically-effective amount of a degradative autophagy agonist or a secretory autoophagy antagonist was described.
Abstract: In one embodiment, the invention provides a method of treating a subject suffering from a Mycobacterium infection by administering to the subject a therapeutically-effective amount of a degradative autophagy agonist or a secretory autophagy antagonist. In another embodiment, the invention provides a method of treating a subject suffering from one or more diseases selected from the group consisting of a Mycobacterium infection, an inflammatory disorder, an immune disorder, a cancer and a neurodegenerative disorder by administering to the subject a therapeutically-effective amount of a TBK-1 antagonist (e.g. BX795 or amlexanox). Related pharmaceutical compositions, diagnostic and screening assays and kits are also provided.
21 citations
TL;DR: Kate Schroder’s laboratory integrates molecular and cell biology approaches with in vivo studies to gain a holistic understanding of inflammasome function during infection, and inflammaome dysfunction in human inflammatory disease.
2 citations