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TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1

Juncal Garcia-Garcia1, Anne Kristin McLaren Berge1, Katrine Stange Overå1

  • 1Department of Medical Biology, Autophagy Research Group, University of Tromsø -The Arctic University of Norway, Norway.

The FEBS Journal
|September 16, 2022
PubMed

Insights

Tripartite motif-containing protein 27 (TRIM27) facilitates mitochondrial clustering and mitophagy by interacting with SQSTM1/p62 and stabilizing phosphorylated TBK1. This reveals new roles for TRIM27 in cellular quality control and innate immunity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Tripartite motif-containing protein 27 (TRIM27), also known as RFP, is a ubiquitin E3 ligase with diverse cellular roles including immune response and apoptosis.
  • TRIM27 interacts with TANK-binding kinase 1 (TBK1), a kinase crucial for innate immunity and mitophagy.
  • TBK1 is involved in recruiting autophagy machinery to damaged mitochondria for degradation (mitophagy).

Purpose of the Study:

  • To investigate the role of TRIM27 in mitophagy.
  • To elucidate the mechanism by which TRIM27 influences mitochondrial quality control.
  • To understand the interplay between TRIM27, TBK1, and autophagy receptors in regulating mitophagy.

Main Methods:

  • Identification of TRIM27 as an autophagy substrate using ATG7, ATG9, and autophagy receptors.
  • Co-localization studies of ubiquitylated TRIM27 with autophagy receptors.
  • Analysis of mitochondrial clustering induced by TRIM27 expression in knockout cells.
  • Investigating the interaction between TRIM27, SQSTM1/p62, and TBK1.
  • Assessing mitophagy activity in TRIM27 knockout and reconstituted cells, with and without TBK1 inhibition.

Main Results:

  • TRIM27 is degraded via the autophagy-lysosomal pathway and forms ubiquitylated bodies that co-localize with autophagy receptors.
  • TRIM27 expression induces mitochondrial clustering, mediated by SQSTM1/p62.
  • Phosphorylated TBK1 is recruited to these clustered mitochondria.
  • TRIM27 knockout cells show reduced mitophagy, which is restored upon TRIM27 re-introduction.
  • TBK1 inhibition impairs mitophagy in cells expressing TRIM27 but not in TRIM27 knockout cells.

Conclusions:

  • TRIM27 acts as an autophagy substrate, playing a novel role in mitophagy.
  • TRIM27 facilitates mitochondrial clustering through SQSTM1/p62.
  • TRIM27 promotes mitophagy by stabilizing phosphorylated TBK1 on mitochondria.
  • These findings highlight TRIM27 as a key regulator linking mitochondrial dynamics, autophagy, and innate immunity.
Keywords:
SQSTM1/p62TBK1TRIM27autophagymitophagy

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