Phosphorylation of phase-separated p62 our bodies by ULK1 prompts a… – Weblog • by NanoWorld®

Liquid–liquid phase-separated biomolecular condensates, liquid droplets play an essential position in lots of organic processes, akin to gene expression, protein translation, stress response, and protein degradation, by incorporating quite a lot of RNA and shopper proteins into their inside relying on the intracellular context. *

Autophagy is concerned within the degradation of a number of cytoplasmic liquid droplets, together with stress granules and P our bodies, and defects on this course of are thought to trigger transition of those droplets to the strong part, ensuing within the growth of intractable ailments akin to neurodegenerative problems and most cancers. *

Of the droplets which have a novel organic perform and are degraded by autophagy, p62 our bodies (additionally known as p62 droplets) are liquid droplets shaped by liquid–liquid part separation (LLPS) of p62 and its binding companions, ubiquitinated proteins. *

p62 our bodies are concerned within the regulation of intracellular proteostasis via their very own autophagic degradation, and likewise contribute to the regulation of the most important stress-response mechanism by sequestration of a shopper protein, kelch-like ECH-associated protein 1 (KEAP1). *

NRF2 is a transcription issue answerable for antioxidant stress responses that’s normally regulated in a redox-dependent method. p62 our bodies shaped by liquid–liquid part separation comprise Ser349-phosphorylated p62, which participates within the redox-independent activation of NRF2. *

Nevertheless, the regulatory mechanism and physiological significance of p62 phosphorylation stay unclear. *

Within the article “Phosphorylation of phase-separated p62 our bodies by ULK1 prompts a redox-independent stress response” Ryo Ikeda, Daisuke Noshiro, Hideaki Morishita, Shuhei Takada, Shun Kageyama, Yuko Fujioka, Tomoko Funakoshi, Satoko Komatsu-Hirota, Ritsuko Arai, Elena Ryzhii, Manabu Abe, Tomoaki Koga, Hozumi Motohashi, Mitsuyoshi Nakao, Kenji Sakimura, Arata Horii, Satoshi Waguri, Yoshinobu Ichimura, Nobuo N Noda and Masaaki Komatsu establish ULK1 as a kinase answerable for the phosphorylation of p62. *

ULK1 colocalizes with p62 our bodies, straight interacting with p62. ULK1-dependent phosphorylation of p62 permits KEAP1 to be retained inside p62 our bodies, thus activating NRF2. p62S351E/+ mice are phosphomimetic knock-in mice wherein Ser351, akin to human Ser349, is changed by Glu. *

These mice, however not their phosphodefective p62S351A/S351A counterparts, exhibit NRF2 hyperactivation and development retardation. This retardation is attributable to malnutrition and dehydration resulting from obstruction of the esophagus and forestomach secondary to hyperkeratosis, a phenotype additionally noticed in systemic Keap1-knockout mice. *

The authors’ outcomes broaden our understanding of the physiological significance of the redox-independent NRF2 activation pathway and supply new insights into the position of part separation on this course of. *

To make clear whether or not the ULK1 kinase itself has an impact on the bodily properties and physiological position of p62 our bodies, Ryo Ikeda et al. first studied the bodily interplay of p62 with ULK1 or its yeast homolog Atg1 utilizing high-speed atomic drive microscopy (HS-AFM). *

HS-AFM of p62 (268–440 aa) visualized a homodimeric construction, mediated by the dimerization of the UBA area, that shaped a hammer-shaped construction with IDRs wrapped round one another. *

HS-AFM photos have been acquired in tapping mode utilizing a sample-scanning HS-AFM instrument. NanoWorld Extremely-Brief Cantilevers of the  USC-F1.2-k0.15 AFM probe sort have been used. ( ~7 μm lengthy, ~2 μm extensive, and ~0.08 μm thick with electron beam-deposited (EBD) suggestions (tip radius < 10 nm). Their resonant frequency and spring fixed have been 1.2 MHz in air and 0.15 N/m, respectively.*

*Ryo Ikeda, Daisuke Noshiro, Hideaki Morishita, Shuhei Takada, Shun Kageyama, Yuko Fujioka, Tomoko Funakoshi, Satoko Komatsu-Hirota, Ritsuko Arai, Elena Ryzhii, Manabu Abe, Tomoaki Koga, Hozumi Motohashi, Mitsuyoshi Nakao, Kenji Sakimura, Arata Horii, Satoshi Waguri, Yoshinobu Ichimura, Nobuo N Noda and Masaaki Komatsu
Phosphorylation of phase-separated p62 our bodies by ULK1 prompts a redox-independent stress response
The EMBO Journal (2023)42:e113349
DOI: https://doi.org/10.15252/embj.2022113349

The article “Phosphorylation of phase-separated p62 our bodies by ULK1 prompts a redox-independent stress response” by Ryo Ikeda, Daisuke Noshiro, Hideaki Morishita, Shuhei Takada, Shun Kageyama, Yuko Fujioka, Tomoko Funakoshi, Satoko Komatsu-Hirota, Ritsuko Arai, Elena Ryzhii, Manabu Abe, Tomoaki Koga, Hozumi Motohashi, Mitsuyoshi Nakao, Kenji Sakimura, Arata Horii, Satoshi Waguri, Yoshinobu Ichimura, Nobuo N Noda and Masaaki Komatsu is licensed beneath a Inventive Commons Attribution 4.0 Worldwide License, which allows use, sharing, adaptation, distribution and replica in any medium or format, so long as you give acceptable credit score to the unique writer(s) and the supply, present a hyperlink to the Inventive Commons license, and point out if modifications have been made. The pictures or different third-party materials on this article are included within the article’s Inventive Commons license, except indicated in any other case in a credit score line to the fabric. If materials shouldn’t be included within the article’s Inventive Commons license and your meant use shouldn’t be permitted by statutory regulation or exceeds the permitted use, you’ll need to acquire permission straight from the copyright holder. To view a duplicate of this license, go to https://creativecommons.org/licenses/by/4.0/.