Research
Proteins are the main components of living organisms. Synthesized proteins do not work in the body for their entire lifetime; most proteins are degraded in a few days and replaced by newly synthesized proteins to maintain biological homeostasis. However, due to various factors such as stress on proteins and genetic mutations, aberrant proteins accumulate like garbage. To prevent this, our body has a garbage-cleaning system (protein quality control mechanism) that degrades and removes aberrant proteins. It is believed that the protein quality control system works to prevent neurodegenerative diseases such as Alzheimer's disease and aging. However, the details of the garbage-cleaning system are not well understood. To elucidate the garbage-cleaning system, we are studying the protein quality control system using mammalian cell culture systems and mice.
Protein quality control system : Synthesized proteins fold into the proper shape and form the correct three-dimensional structure to function. However, when the three-dimensional structure is broken due to damage or aging, it is transformed into an aberrant protein. When aberrant proteins accumulate, cells and organs cannot function properly, causing various diseases and aging. To prevent the accumulation of such aberrant proteins, a protein quality control system exists in the body that recognizes aberrant proteins and leads them to proteolysis.
Research Objectives Humans have approximately 20,000 genes, each of which is synthesized into unique proteins. Proteins in mammals vary widely in shape and localization in different spaces, including intracellular proteins, intracellular organelles, extracellular region. Therefore, each aberrant protein must be recognized and degraded by a specific mechanism. What is the mechanism by which each aberrant protein is recognized and targeted for degradation? Many questions remain unanswered. We are investigating the extracellular protein degradation system by which aberrant proteins in blood and body fluids are recognized and degraded by the endocytosis/lysosome system, and the autophagy/lysosome system by which intracellular proteins are degraded, using cultured mammalian cells and mice. Our goal is to comprehensively elucidate the protein quality control system.
Our works
(selected publications)
Extracellular protein degradation system
Itakura E#, Chiba M, Murata T, Matsuura A. (#single corresponding author)
Heparan sulfate is a clearance receptor for aberrant extracellular proteins.
J Cell Biol. 2020 Mar 2;219(3). pii: e201911126. doi: 10.1083/jcb.201911126.
We found that heparan sulfate on the plasma membrane is a receptor for lysosomal degradation of Clusterin and aberrant protein complexes to degrade extracellular aberrant proteins, leading to an extracellular protein quality control pathway by the CRED pathway.
Tomihari A*, Chiba M*, Matsuura A, Itakura E.Protocol for quantification of the lysosomal degradation of extracellular proteins into mammalian cells.
STAR Protoc. 2021 Nov 23;2(4):100975. doi: 10.1016/j.xpro.2021.100975.
A fluorescent tag protein uptake assay method was developed.
Tomihari A, Kiyota M, Matsuura A, Itakura E.
Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins.
Sci Rep. 2023 Mar 28;13(1):4680. doi: 10.1038/s41598-023-31104-x.
We found that α2macroglobulin is a factor that leads to degradation of extracellular misfolded proteins.
Intracellular protien degaradation system (autophagy)
Takayama K, Matsuura A, Itakura
Dissection of ubiquitinated protein degradation by basal autophagy
FEBS Lett. 2017 May;591(9):1199-1211
Tatsumi T, Takayama K, Ishii S, Yamamoto A, Hara T, Minami N, Miyasaka N, Kubota T, Matsuura A, Itakura E# & Tsukamoto S# ( #co-corresponding authors)
Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse
Development 2018 Feb 23;145(4). pii: dev161893.
We developed forced lipophagy and found that lipolytic degradation is involved during early development of mouse fertilized eggs.
Ishii S, Matsuura A, Itakura E.
Identification of a factor controlling lysosomal homeostasis using a novel lysosomal trafficking probe.
Sci Rep. 2019 Aug 12;9(1):11635. doi: 10.1038/s41598-019-48131-2.
A Lysosomal-METRIQ probe was developed for quantitative analysis of lysosomal degradation activity in mammalian cells.
Uesugi R, Ishii S, Matsuura A, Itakura E.
Labeling and measuring stressed mitochondria using a PINK1-based ratiometric fluorescent sensor.
J Biol Chem. 2021 Nov;297(5):101279. doi: 10.1016/j.jbc.2021.101279.
Mitochondrial stress probe Mito-Pain was developed and mitochondrial stress-related compounds were discovered.
Date Y, Matsuura A, Itakura E.
Disruption of actin dynamics induces autophagy of the eukaryotic chaperonin TRiC/CCT.
Cell Death Discov. 2022 Jan 25;8(1):37. doi: 10.1038/s41420-022-00828-6.
We found that the TRiC complex is degraded by autophagy during abnormal actin polymerization.
Ishii S*, Chino H*, Ode KL, Kurikawa Y, Ueda HR, Matsuura A, Mizushima N, Itakura E.
CCPG1 recognizes endoplasmic reticulum luminal proteins for selective ER-phagy.
Mol Biol Cell. 2023 Apr 1;34(4):ar29. doi: 10.1091/mbc.E22-09-0432.
We found that CCPG1 is a bi-receptor for both aberrant proteins in the lumen of the endoplasmic reticulum and autophagosome membranes.
Chiba M, Yanagawa M, Oyama Y, Harada S, Nemoto T, Matsuura A, Itakura E
A novel autophagy inhibitor, bTBT, disturbs autophagosome formation.
Autophagy Rep. 2023 Apr 6;2(1):2194620.
The autophagy inhibitor compound bis-tributyltin was identified.