Ubiquitin-specific protease USP36 knockdown impairs Parkin-dependent mitophagy via downregulation of Beclin-1-associated autophagy-related ATG14L

Autor: Anna Lechado Terradas, Friederike Hans, Sonia Golombek, Sven Geisler, Caren Linnemann, Etsuro Nakanishi, Lea Jäger, Nicolas Casadei, Philipp J. Kahle
Rok vydání: 2019
Předmět:
0301 basic medicine
Autophagy-Related Proteins
Mitochondrion
Parkin
Deubiquitinating enzyme
0302 clinical medicine
Ubiquitin
Mitophagy
genetics [Ubiquitin]
genetics [Ubiquitin-Specific Proteases]
genetics [Ubiquitination]
genetics [Ubiquitin-Protein Ligases]
Gene knockdown
biology
Mitochondria
Ubiquitin ligase
Cell biology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Beclin-1
genetics [Mitochondrial Proteins]
Ubiquitin-Specific Proteases
Ubiquitin Thiolesterase
genetics [Adaptor Proteins
Vesicular Transport]
genetics [Autophagy]
Ubiquitin-Protein Ligases
genetics [Autophagy-Related Proteins]
Down-Regulation
methods [Gene Knockdown Techniques]
Mitochondrial Proteins
genetics [Ubiquitin Thiolesterase]
03 medical and health sciences
ddc:570
Cell Line
Tumor
Autophagy
Humans
Ubiquitination
Cell Biology
nervous system diseases
Adaptor Proteins
Vesicular Transport
030104 developmental biology
genetics [Beclin-1]
biology.protein
genetics [Mitochondria]
genetics [Down-Regulation]
HeLa Cells
genetics [Mitophagy]
Zdroj: Experimental cell research 384(2), 111641 (2019). doi:10.1016/j.yexcr.2019.111641
ISSN: 0014-4827
DOI: 10.1016/j.yexcr.2019.111641
Popis: Parkin is an ubiquitin ligase regulating mitochondrial quality control reactions, including the autophagic removal of depolarized mitochondria (mitophagy). Parkin-mediated protein ubiquitinations may be counteracted by deubiquitinating enzymes (DUBs). We conducted a high-content imaging screen of Parkin translocation to depolarized mitochondria after siRNA mediated silencing of each DUB in Parkin overexpressing HeLa cells. Knockdown of the ubiquitin-specific protease USP36 led to delayed Parkin translocation while only slightly disturbing the ubiquitination of mitochondrial proteins, but final autophagic elimination of mitochondria was severely disrupted. The localization of the nucleolar USP36 was not altered during mitophagy. However, the marker for transcriptional active chromatin, histone 2B Lys120 mono-ubiquitination was found reduced in USP36-silenced cells undergoing mitophagy. We observed a reduction of the mRNA and protein levels of Beclin-1 and its associated autophagy-related key regulator ATG14L in USP36 knockdown cells. Importantly, transfection of active ATG14L into USP36-silenced cells significantly restored Parkin-dependent mitophagy. We propose USP36 as regulator for the Parkin-dependent mitophagy at least in part via the Beclin-1-ATG14L pathway.
Databáze: OpenAIRE
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