The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation

Waku, Tsuyoshi; Nakada, Sota; Masuda, Haruka; Sumi, Haruna; Wada, Ayaka; Hirose, Shuuhei; Aketa, Iori; Kobayashi, Akira

doi:10.1016/j.celrep.2022.111906

“…Additionally, we have identified some candidate genes that likely control the feather colors of Wenchang chickens. For instance, we found a candidate gene for yellow feathers, GABARAPL2 , which contributes to the formation of autophagosomes, thus forming melanosomes ( Schaaf et al., 2016 ; Waku et al., 2023 ). In mice, mutations in LYST (a yellow feather candidate gene in Wenchang chickens) cause melanosomes to become larger, leading to reduced melanosis ( Barbosa et al., 1996 ; Perou et al., 1996 ; Runkel et al., 2006 ; Trantow et al., 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Genomic insights into local adaptation and phenotypic diversity of Wenchang chickens

Gu,

Wu,

Zheng

et al. 2024

Poultry Science

8

0

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“…NRF1-related proteins have been implicated in the regulation of autophagy in various biological events because several autophagy-related genes carry ARE sites recognized by these proteins 38 . For instance, we have recently demonstrated that NRF3 coordinates the melanogenesis cascade by activating the expression of autophagy-related genes such as GABARAPL2 and ULK2 , which are required for the formation of autophagosomes 39 . NRF2 also modulates the expression of autophagy-related genes to eliminate protein aggregates 38 .…”

Section: Discussionmentioning

confidence: 99%

The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis

Hatanaka,

Nakada,

Matsumoto

et al. 2023

Sci Rep

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The ubiquitin‒proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood. Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62/SQSTM1 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of Ser403 in p62. Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.

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“…NRF1related proteins have been implicated in the regulation of autophagy in various biological events because several autophagy-related genes carry ARE sites recognized by these proteins 37 . For instance, we have recently demonstrated that NRF3 coordinates the melanogenesis cascade by activating the expression of autophagy-related genes such as GABARAPL2 and ULK2, which are required for the formation of autophagosomes 38 . NRF2 also modulates the expression of autophagy-related genes to eliminate protein aggregates 37 .…”

Section: Discussionmentioning

confidence: 99%

The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducingp62 and GABARAPL1 after proteasome inhibition to maintain proteostasis

Hatanaka

¹

,

Nakada

²

,

Matsumoto

³

et al. 2023

Preprint

Self Cite

1

0

View full text Add to dashboard Cite

The ubiquitin‒proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood. Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62/SQSTM1 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of Ser403 in p62. Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.

show abstract

The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation

Cited by 8 publications

References 75 publications

Genomic insights into local adaptation and phenotypic diversity of Wenchang chickens

Genomic insights into local adaptation and phenotypic diversity of Wenchang chickens

The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis

The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducingp62 and GABARAPL1 after proteasome inhibition to maintain proteostasis

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