Journal Article

DZNE-2020-03846

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The ubiquitin-conjugating enzymes UBE2N, UBE2L3 and UBE2D2/3 are essential for Parkin-dependent mitophagy.

Geisler, S. (Corresponding author) ; Vollmer, S. ; Golombek, S. ; Kahle, P. J. (Last author)DZNE*

2014
Company of Biologists Limited Cambridge

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Please use a persistent id in citations: doi:10.1242/jcs.146035

Abstract: Depolarized mitochondria are degraded by mitophagy in a process that depends on the Parkinson's disease gene products PINK1 and Parkin. This is accompanied by ubiquitylation of several mitochondrial substrates. The roles of E2 ubiquitin-conjugating enzymes (UBE2) in mitophagy are poorly understood. Here, we investigate a set of UBE2 enzymes that might regulate Parkin-mediated mitophagy. Knockdown of the E2 enzymes UBE2N, UBE2L3 or UBE2D2 and UBE2D3 (UBE2D2/3) significantly reduced autophagic clearance of depolarized mitochondria. However, this did not interfere with mitochondrial PINK1 stabilization and Parkin translocation. UBE2N knockdown prevented specifically K63-linked ubiquitylation at mitochondrial sites. Nevertheless, polyubiquitin and p62 (officially known as SQSTM1) were still found on mitochondria after individual UBE2 knockdown. Knockdown of all of these UBE2s together significantly reduced mitochondrial polyubiquitylation and p62 recruitment. Moreover, reduced ubiquitylation of mitofusins, the mitochondrial import receptor subunits TOM20 and TOM70, the voltage-dependent anion channel protein 1 and Parkin was observed in cells silenced for all of these UBE2s. A version of Parkin with a mutation in the active site (C431S) failed to ubiquitylate these mitochondrial substrates even in the presence of UBE2s. We conclude that UBE2N, UBE2L3 and UBE2D2/3 synergistically contribute to Parkin-mediated mitophagy.

Keyword(s): Mitochondrial Precursor Protein Import Complex Proteins (MeSH) ; HeLa Cells (MeSH) ; Homeostasis (MeSH) ; Humans (MeSH) ; Membrane Potential, Mitochondrial (MeSH) ; Membrane Transport Proteins: metabolism (MeSH) ; Mitochondria: physiology (MeSH) ; Mitochondrial Membrane Transport Proteins: metabolism (MeSH) ; Mitophagy: genetics (MeSH) ; Mutation: genetics (MeSH) ; Parkinson Disease: enzymology (MeSH) ; Parkinson Disease: genetics (MeSH) ; Protein Kinases: metabolism (MeSH) ; RNA, Small Interfering: genetics (MeSH) ; Receptors, Cell Surface: metabolism (MeSH) ; Ubiquitin-Conjugating Enzymes: metabolism (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; Ubiquitination: genetics (MeSH) ; Voltage-Dependent Anion Channel 1: metabolism (MeSH) ; Membrane Transport Proteins ; Mitochondrial Membrane Transport Proteins ; RNA, Small Interfering ; Receptors, Cell Surface ; TOMM20 protein, human ; TOMM70 protein, human ; Voltage-Dependent Anion Channel 1 ; UBE2D2 protein, human ; UBE2L3 protein, human ; UBE2N protein, human ; Ubiquitin-Conjugating Enzymes ; Ubiquitin-Protein Ligases ; parkin protein ; Protein Kinases ; PTEN-induced putative kinase

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Contributing Institute(s):

1. Functional Neurogenetics (AG Kahle 2)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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