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NIPSNAP1 and NIPSNAP2 Act as “Eat Me” Signals for Mitophagy

alfy autophagy mitophagy nipsnap1 nipsnap2 p62/sqstm1 parkin ndp52 optineurin tax1bp1

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#1 Engadin

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Posted 23 April 2019 - 09:13 PM


Highlights
  • The mitochondria proteins NIPSNAP1 and NIPSNAP2 bind to autophagy-related proteins
  • NIPSNAP1 and NIPSNAP2 recruit autophagy receptors to depolarized mitochondria
  • NIPSNAP1 and NIPSNAP2, acting redundantly, are required for PARKIN-dependent mitophagy
  • Nipsnap1-deficient zebrafish larvae display parkinsonism
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Summary
The clearance of damaged or dysfunctional mitochondria by selective autophagy (mitophagy) is important for cellular homeostasis and prevention of disease. Our understanding of the mitochondrial signals that trigger their recognition and targeting by mitophagy is limited. Here, we show that the mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and NIPSNAP2 accumulate on the mitochondria surface upon mitochondrial depolarization. There, they recruit proteins involved in selective autophagy, including autophagy receptors and ATG8 proteins, thereby functioning as an “eat me” signal for mitophagy. NIPSNAP1 and NIPSNAP2 have a redundant function in mitophagy and are predominantly expressed in different tissues. Zebrafish lacking a functional Nipsnap1 display reduced mitophagy in the brain and parkinsonian phenotypes, including loss of tyrosine hydroxylase (Th1)-positive dopaminergic (DA) neurons, reduced motor activity, and increased oxidative stress.
 
Graphical Abstract

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Introduction
Macroautophagy (hereafter autophagy) involves sequestration of cytoplasmic cargo into autophagosomes that fuse with lysosomes for degradation ( ). Autophagy is needed for survival upon cellular stress and has an important housekeeping function by selective removal of damaged or dysfunctional components. Selective autophagy employs specific autophagy receptors that recognize the cargo to become degraded ( ). Sequestosome-1 (hereafter referred to as p62), the best studied autophagy receptor, is implicated in clearance of many types of ubiquitinated cargos, including aggregate-prone proteins ( ), mitochondria ( ), bacteria ( ), and midbody remnants ( ). Autophagy receptors contain a light chain 3 (LC3)-interacting region (LIR) mediating their interaction with microtubule-associated protein 1 LC3 and/or GABA type A receptor-associated protein (GABARAP) family proteins in the autophagy membrane ( ). Selective autophagy may also require autophagy adaptor proteins, which possess an LIR but are themselves not degraded by autophagy ( ). One such adaptor protein is the large scaffolding protein autophagy-linked FYVE (ALFY), which binds GABARAP and phosphatidylinositol-3-phosphate (PtdIns3P) ( ), as well as p62 and neighbor of BRCA1 gene 1 (NBR1) ( ), and is important for selective clearance of protein aggregates ( ), midbody remnants ( ), and viral particles ( ).
Turnover of mitochondria through autophagy (mitophagy) is important for cellular homeostasis, particularly in post-mitotic and slow dividing cells, such as neurons and cardiomyocytes. Causative mutations in two proteins involved in mitophagy, the E3 ubiquitin ligase PARKIN and PTEN-induced putative kinase 1 (PINK1), are linked to Parkinson’s disease (PD) ( ). PINK1 is stabilized on the outer mitochondrial membrane (OMM) after loss of mitochondrial membrane potential, where it phosphorylates ubiquitin ( ) and PARKIN ( ), leading to PARKIN activation and further K63-linked poly-ubiquitination of mitochondrial substrate(s). This is followed by the recruitment of autophagy receptors, including optineurin (OPTN) and nuclear dot protein 52 (NDP52) (also called CALCOCO2) ( ). While p62 and NBR1 seem dispensable for PARKIN-dependent mitophagy in HeLa cells ( ), p62 is essential for PARKIN-dependent mitophagy in macrophages treated with inflammasome NLRP3 agonists ( ), suggesting cell- or context-specific variations in employment of autophagy receptors in mitophagy. Little is known about the mitochondrial signals that trigger recruitment of autophagy receptors and mitophagy. Recently, the inner mitochondrial membrane protein, prohibitin 2 (PHB2) was found to bind LC3 upon OMM rupture and function as a receptor for PARKIN-dependent mitophagy ( ). In this study, we identify the mitochondrial matrix proteins NIPSNAP1 and NIPSNAP2 as “eat me” signals for damaged mitochondria via their recruitment of autophagy receptors and show that NIPSNAP1 and NIPSNAP2 have redundant roles in PARKIN-dependent mitophagy and a neuroprotective function in vivo.

Rest at the source: https://www.cell.com...5807(19)30224-2







Also tagged with one or more of these keywords: alfy, autophagy, mitophagy, nipsnap1, nipsnap2, p62/sqstm1, parkin, ndp52, optineurin, tax1bp1

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