2. Academic Validation
  3. TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1

TNIP1 inhibits selective autophagy via bipartite interaction with LC3/GABARAP and TAX1BP1

  • Mol Cell. 2023 Mar 16;83(6):927-941.e8. doi: 10.1016/j.molcel.2023.02.023.
François Le Guerroué 1,  Eric N Bunker 1,  William M Rosencrans 2,  Jack T Nguyen 3,  Mohammed A Basar 4,  Achim Werner 4,  Tsui-Fen Chou 3,  Chunxin Wang 1,  Richard J Youle 5
Affiliations

Affiliations

  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • 3 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • 4 Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: youler@ninds.nih.gov.
PMID: 36898370 DOI: 10.1016/j.molcel.2023.02.023
Abstract

Mitophagy is a form of selective Autophagy that disposes of superfluous and potentially damage-inducing organelles in a tightly controlled manner. While the machinery involved in Mitophagy induction is well known, the regulation of the components is less clear. Here, we demonstrate that TNIP1 knockout in HeLa cells accelerates Mitophagy rates and that ectopic TNIP1 negatively regulates the rate of Mitophagy. These functions of TNIP1 depend on an evolutionarily conserved LIR motif as well as an AHD3 domain, which are required for binding to the LC3/GABARAP family of proteins and the Autophagy receptor TAX1BP1, respectively. We further show that phosphorylation appears to regulate its association with the ULK1 complex member FIP200, allowing TNIP1 to compete with Autophagy receptors, which provides a molecular rationale for its inhibitory function during Mitophagy. Taken together, our findings describe TNIP1 as a negative regulator of Mitophagy that acts at the early steps of autophagosome biogenesis.

Keywords

FIP200; FIR; LIR; Selective autophagy; TAX1BP1; TBK1; TNIP1; mitophagy; mitophagy regulation.

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