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Browsing by Subject "GABARAP"
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Item Measurement of the Activity of the ATG4 Cysteine Proteases(Elsevier, 2017) Li, Min; Fu, Yuanyuan; Yang, Zuolong; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineWhile only one Atg4 is present in yeast, there are four Atg4 homologues in human and in mouse with different substrate specificities and catalytic efficiencies. The molecule Atg4 is a type of cysteine protease, and is known for its crucial roles in cleavage of the Atg8 family proteins before they can be conjugated to phospholipids, and also in cleavage of the conjugated Atg8 molecules from the membrane, a process known as deconjugation. Both processes are required for the maximal efficiency in autophagosome biogenesis. Atg4 could thus be a target for intervention of the autophagy process. It is thus important to measure Atg4 activity to determine and to modulate the autophagy function. Here we review the catalytic functions and regulatory mechanisms of human Atg4 proteases, and discuss the methodology for analyzing Atg4 activity in details.Item RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss(Elsevier, 2022) Li, Jinan; Liu, Chang; Müller, Ulrich; Zhao, Bo; Otolaryngology -- Head and Neck Surgery, School of MedicineAminoglycosides (AGs) are potent antibiotics capable of treating a wide variety of life-threatening infections, however, they are ototoxic and cause irreversible damage to cochlear hair cells. Despite substantial progress, little is known about the molecular pathways critical for hair cell function and survival that are affected by AG exposure. We demonstrate here that gentamicin, a representative AG antibiotic, binds to and triggers within minutes translocation of RIPOR2 in murine hair cells from stereocilia to the pericuticular area. Then, by interacting with a central autophagy component GABARAP, RIPOR2 affects autophagy activation. Reducing the expression of RIPOR2 or GABARAP completely prevents AG-induced hair cell death and subsequent hearing loss in mice. Additionally, abolishing the expression of PINK1 or Parkin, two key mitochondrial autophagy proteins, prevents hair cell death and subsequent hearing loss caused by AG. In summary, our study demonstrates that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss.Item RIPOR2-mediated autophagy dysfunction is critical for aminoglycoside-induced hearing loss(Elsevier, 2022-09-26) Li , Jinan; Liu , Chang; Müller , Ulrich; Zhao, Bo; Otolaryngology -- Head and Neck Surgery, School of MedicineAminoglycosides (AGs) are potent antibiotics that are capable of treating a wide variety of life-threatening infections; however, they are ototoxic and cause irreversible damage to cochlear hair cells. Despite substantial progress, little is known about the molecular pathways critical for hair cell function and survival that are affected by AG exposure. We demonstrate here that gentamicin, a representative AG antibiotic, binds to and within minutes triggers translocation of RIPOR2 in murine hair cells from stereocilia to the pericuticular area. Then, by interacting with a central autophagy component, GABARAP, RIPOR2 affects autophagy activation. Reducing the expression of RIPOR2 or GABARAP completely prevents AG-induced hair cell death and subsequent hearing loss in mice. Additionally, abolishing the expression of PINK1 or Parkin, two key mitochondrial autophagy proteins, prevents hair cell death and subsequent hearing loss caused by AG. In summary, our study demonstrates that RIPOR2-mediated autophagic dysfunction is essential for AG-induced hearing loss.