A5000718732- interferon and immune responses
- Viral Infections and Vectors
- Inflammasome and immune disorders
- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Calcium signaling and nucleotide metabolism
- Lipid Membrane Structure and Behavior
- Toxoplasma gondii Research Studies
- Immune Response and Inflammation
- Amino Acid Enzymes and Metabolism
- Metabolism and Genetic Disorders
- Erythrocyte Function and Pathophysiology
- Sphingolipid Metabolism and Signaling
- Biochemical Acid Research Studies
- Lysosomal Storage Disorders Research
- Viral Infections and Outbreaks Research
- Retinal Development and Disorders
- Herpesvirus Infections and Treatments
- Mosquito-borne diseases and control
- Biomedical Research and Pathophysiology
- Influenza Virus Research Studies
- CRISPR and Genetic Engineering
- Microtubule and mitosis dynamics
Tohoku University
2016-2025
University of California, San Diego
2017
Abstract Coat protein complex I (COP-I) mediates the retrograde transport from Golgi apparatus to endoplasmic reticulum (ER). Mutation of COPA gene, encoding one COP-I subunits (α-COP), causes an immune dysregulatory disease known as syndrome. The molecular mechanism by which impaired results in autoinflammation remains poorly understood. Here we report that STING, innate immunity protein, is a cargo membrane transport. In presence disease-causative α-COP variants, STING cannot be retrieved...
Abstract Stimulator of interferon genes (STING) is essential for the type I response against a variety DNA pathogens. Upon emergence cytosolic DNA, STING translocates from endoplasmic reticulum to Golgi where activates downstream kinase TBK1, then lysosome through recycling endosomes (REs) its degradation. Although molecular machinery activation extensively studied and defined, one underlying degradation inactivation has not yet been fully elucidated. Here we show that degraded by endosomal...
Abstract Stimulator of interferon genes (STING) is critical for the type I response to pathogen- or self-derived DNA in cytosol. STING may function as a scaffold activate TANK-binding kinase 1 (TBK1), but direct cellular evidence remains lacking. Here we show, using single-molecule imaging with enhanced time resolutions down 5 ms, that becomes clustered at trans-Golgi network (about 20 molecules per cluster). The clustering requires palmitoylation and Golgi lipid order defined by...
Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite ongoing remodeling that occurs with atrophy, damage aging. We uncovered an essential role autophagy T-tubule genetic screens developmentally regulated program Drosophila abdominal muscles. Here, we show both...
The Rab family of small GTPases comprises the largest number proteins (∼60 in mammals) among regulators intracellular membrane trafficking, but precise function many Rabs and functional redundancy diversity remain largely unknown. Here, we generated a comprehensive collection knockout (KO) MDCK cells for entire family. We knocked out closely related paralogs simultaneously (Rab subfamily knockout) to circumvent compensation found that Rab1A/B Rab5A/B/C are critical cell survival and/or...
Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In portion the cytoplasm wrapped by autophagosome, then fuses with delivers engulfed CMA, translocation cytosolic substrates lysosomal lumen directly across limiting membrane lysosomes. microautophagy, lytic organelles, including endosomes or lysosomes, take up...
COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% individuals, with no known mediators protection. Recent studies implicate STING the pathogenesis syndrome. We show that common HAQ allele mediates complete clinical sequenced 35 individuals mutations, 26 affected patients and 9 unaffected carriers, finding co-segregation nonpenetrance. Exome sequencing identified only mutations comprising as variants shared by carriers absent patients. Experimentally, we...
Tunneling nanotubes (TNTs) are actin-enriched membranous channels enabling cells to communicate over long distances. TNT-like structures form between various cell types and mediate the exchange of different cargos, such as ions, vesicles, organelles, pathogens. Thus, they may play a role in physiological conditions diseases (e.g., cancer infection). TNTs also allow intercellular passage protein aggregates related neurodegenerative diseases, thus propagating misfolding. Understanding...
Stimulator of interferon genes (STING) triggers the type I and inflammatory responses against a variety DNA pathogens, which is essential to limiting viral infection replication. STING activates downstream kinase TBK1 at trans-Golgi network (TGN) degraded lysosomes through process called lysosomal microautophagy. Impaired targeting results in prolonged signal, may be associated with neurodegenerative autoinflammatory diseases. Thus, development methods quantify degradation helps understand...
Macroautophagy (simply called autophagy hereafter) is an intracellular degradation mechanism that activated by nutrient starvation. Although it well known starvation induces autophagosome formation in mTORC1-dependent manner, whether also regulates or autolysosome maturation was unclear. In the present study, we succeeded demonstrating activates mammalian cells. We found knockout (KO) of Rab7 (herein referring to Rab7a isoform) caused accumulation a massive number LC3-positive autolysosomes...
Summary Our body is constantly exposed to pathogens, and equipped with a highly elaborate immune system fight against invading pathogens. The first line of defense the innate system. It has evolved detect conserved microbial molecular patterns, dubbed pathogen-associated patterns (PAMPs), through pattern recognition receptors (PRRs). binding PRRs PAMPs activates intracellular signalling cascades that lead expression proinflammatory cytokines, type I interferons, other antiviral proteins all...
Stimulator of interferon genes (STING) is essential for the type I response induced by microbial DNA or self-DNA leaked from mitochondria/nuclei. In to emergence such DNAs in cytosol, STING relocates endoplasmic reticulum (ER) Golgi, and activates TANK-binding kinase 1 (TBK1), a cytosolic activation STING-dependent downstream signalling. To understand at which subcellular compartments TBK1 becomes associated with STING, we generated cells stably expressing fluorescent protein-tagged...
Coat protein complex I (COP-I) mediates the retrograde transport from Golgi to ER 1,2 . Mutation of COPA gene, encoding one COP-I subunits (α-COP), causes an immune dysregulatory disease (COPA syndrome) 3 The molecular mechanism by which impaired results in autoinflammation is not understood. Here we report that STING 4 , innate immunity protein, a cargo Golgi-to-ER membrane transport. In presence disease-causative α-COP variants, cannot be retrieved back Golgi. forced residency...
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune pathway has emerged as a critical driver inflammation in variety settings, such virus infection, cellular stress, tissue damage, and aging. detects microbial host-derived double-stranded DNA (dsDNA) the cytosol triggers production type I interferons proinflammatory cytokines that help eliminate invading pathogens. STING is mobile protein. After its binding to GMP-AMP, which generated by cGAS presence...
Abstract Sphingomyelin (SM) is a major sphingolipid in mammalian cells. SM enriched the extracellular leaflet of plasma membrane (PM). Besides this localization, recent electron microscopic and biochemical studies suggest presence cytosolic PM. In present study, we generated non-toxic SM-binding variant (NT-EqtII) based on equinatoxin-II (EqtII) from sea anemone Actinia equina , examined dynamics living cell PMs. NT-EqtII with two point mutations (Leu26Ala Pro81Ala) had essentially same...
Abstract Stimulator of interferon genes (STING) is critical for the type I response to pathogen- or self-derived cytosolic DNA. STING degraded by endosomal sorting complexes required transport (ESCRT)-driven lysosomal microautophagy (LMA), impairment which leads sustained inflammatory responses. It has been unknown how ESCRT targets directly lysosomes. Here, through kinase inhibitor screening and knockdown experiments all individual components ESCRT, we show that degradation requires PIKfyve...
Summary Super-resolution microscopic observation of a novel non-toxic sphingomyelin probe revealed the formation dynamic small domains including and cholesterol in cytosolic leaflet living cell plasma membranes. Abstract Sphingomyelin (SM) is major sphingolipid mammalian cells. SM enriched extracellular membrane (PM). Besides this localization, recent electron biochemical studies suggest presence PM. In present study, we generated SM-binding variant (NT-EqtII) based on equinatoxin-II (EqtII)...
Stimulator of interferon genes (STING) is essential for the type I response induced by microbial DNA from viruses or self-DNA mitochondria/nuclei. Recently, gain-of-function mutations in STING have been identified patients with STING-associated vasculopathy onset infancy (SAVI). The SAVI exhibit complex systemic vascular inflammation and interstitial lung disease, resulting pulmonary fibrosis respiratory failure. mouse models recently developed, harbouring common mutations, such as N153S...
Stimulator of interferon genes (STING) is essential for the type I response against a variety DNA pathogens 1,2 . Upon emergence cytosolic DNA, STING translocates from endoplasmic reticulum (ER) to Golgi where activates downstream kinase TBK1, then lysosome through recycling endosomes (REs) its degradation 3–6 Although molecular machinery activation extensively studied and defined 7 , one underlying has not yet been fully elucidated. Here we show an unanticipated mechanism termed “lysosomal...
Abstract Stimulator of interferon genes (STING) is an innate immune protein for DNA pathogens. In response to the emergence in cytosol, STING relocates from endoplasmic reticulum (ER) Golgi and induces type I through cytosolic TANK-binding kinase 1 (TBK1). The molecular mechanism underlying TBK1 activation by remains poorly understood. Here we report a cell system which are simultaneously monitored. utilizes STING/TBK1-double knockout (KO) cells, fluorescent protein-tagged STING,...