NBR1: The archetypal selective autophagy receptor

Rasmussen, Nikoline Lander; Kournoutis, Athanasios; Lamark, Trond; Johansen, Terje

doi:10.1083/jcb.202208092

Cited by 40 publications

(30 citation statements)

References 108 publications

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“…A comparison of these factors in the regulation of ubiquitin-dependent mitophagy suggested that only NDP52 and OPTN play critical roles ( 4 ). In contrast, ubiquitin-dependent pexophagy relies upon NBR1 ( 5 , 6 ). There is also diversity of mechanisms in pathways converging on organelle turnover.…”

Section: Introductionmentioning

confidence: 99%

Segregation of pathways leading to pexophagy

2023

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Peroxisomes are organelles with key roles in metabolism including long-chain fatty acid production. Their metabolic functions overlap and interconnect with those of mitochondria, with which they share an overlapping but distinct proteome. Both organelles are degraded by selective autophagy processes termed pexophagy and mitophagy. Although mitophagy has received intense attention, the pathways linked to pexophagy and associated tools are less well developed. We have identified the neddylation inhibitor MLN4924 as a potent activator of pexophagy and show that this is mediated by the HIF1α-dependent up-regulation of BNIP3L/NIX, a known adaptor for mitophagy. We show that this pathway is distinct from pexophagy induced by the USP30 deubiquitylase inhibitor CMPD-39, for which we identify the adaptor NBR1 as a central player. Our work suggests a level of complexity to the regulation of peroxisome turnover that includes the capacity to coordinate with mitophagy, via NIX, which acts as a rheostat for both processes.

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Section: Introductionmentioning

confidence: 99%

Segregation of pathways leading to pexophagy

2023

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“…Ezurpimtrostat treatment led to decreased NBR1 protein expression in cancer cells. In addition to the NBR1 mRNA expression found in most cancers, it was associated with low cancer specificity (35,36). NBR1 overexpression increased the proliferation of renal cancer cells in vitro (37) and promoted tumor metastasis in a breast cancer mouse model (38).…”

Section: Discussion/conclusionmentioning

confidence: 99%

Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments

Bestion

Rachid

Tijeras‐Raballand³

et al. 2023

Preprint

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Background: Palmitoyl-protein thioesterase-1 (PPT1) is an exciting druggable target for inhibiting autophagy in cancer. Methods: In this study, we aimed to evaluate the effects of ezurpimtrostat-targeting PPT1 in combination with an anti-PD-1 antibody in liver cancer using a transgenic immunocompetent mouse model. Results: Herein, we revealed that inhibition of PPT1 using ezurpimtrostat, a safe anticancer drug in humans, decreased the liver tumor burden by inducing the penetration of lymphocytes within tumors when combined with anti-programmed death-1 (PD-1). Inhibition of PPT1 potentiates the effects of anti-PD-1 immunotherapy by increasing the expression of major histocompatibility complex (MHC)-I at the surface of liver cancer cells and modulates immunity through recolonization and activation of cytotoxic CD8+ lymphocytes. Conclusions: Ezurpimtrostat turns cold into hot tumors and, thus, constitutes a powerful strategy to improve T cell-mediated immunotherapies in liver cancer.

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“…Protein aggregates also represent ancestral noxious objects dealt with already in prokaryotes through disaggregating enzymes ( 41 ) and may have been among the first targets of this evolving selectiveness, as witnessed by the presence of an ancestral form of NBR1 in the LECA ( 42 ).…”

Section: The Evolution Of Autophagymentioning

confidence: 99%

Autophagy and longevity: Evolutionary hints from hyper-longevous mammals

Locatelli¹,

Cenci

2022

Front. Endocrinol.

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Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging.

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NBR1: The archetypal selective autophagy receptor

Cited by 40 publications

References 108 publications

Segregation of pathways leading to pexophagy

Segregation of pathways leading to pexophagy

Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments

Autophagy and longevity: Evolutionary hints from hyper-longevous mammals

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