iScience. 2023 Aug 29;26(10):107777.  doi: 10.1016/j.isci.2023.107777. eCollection 2023 Oct 20.

ER-trafficking triggers NRF1 ubiquitination to promote its proteolytic activation

Claire Chavarria ¹, Léa Zaffalon ¹, Sérgio T Ribeiro ¹, Mélanie Op ¹, Manfredo Quadroni ², Maria Sofia Iatrou ¹, Chloé Chapuis ¹, Fabio Martinon ¹

Abstract

The transcription factor NRF1 resides in the endoplasmic reticulum (ER) and is constantly transported to the cytosol for proteasomal degradation. However, when the proteasome is defective, NRF1 escapes degradation and undergoes proteolytic cleavage by the protease DDI2, generating a transcriptionally active form that restores proteostasis, including proteasome function. The mechanisms that regulate NRF1 proteolytic activation and transcriptional potential remain poorly understood. This study demonstrates that the ER is a crucial regulator of NRF1 function by orchestrating its ubiquitination through the E3 ubiquitin ligase HRD1. We show that HRD1-mediated NRF1 ubiquitination is necessary for DDI2-mediated processing in cells. Furthermore, we found that deficiency in both RAD23A and RAD23B impaired DDI2-mediated NRF1 processing, indicating that these genes are essential components of the DDI2 proteolytic machinery. Our findings highlight the intricate mechanism by which the ER activates NRF1 to coordinate the transcriptional activity of an adaptation response in cells.

• PMID: 37720101
• PMCID: PMC10502413
• DOI: 10.1016/j.isci.2023.107777

PLoS Biol. 2023 Sep 21;21(9):e3002308.  doi: 10.1371/journal.pbio.3002308. eCollection 2023 Sep.

Hyperglycemia increases SCO-spondin and Wnt5a secretion into the cerebrospinal fluid to regulate ependymal cell beating and glucose sensing

Francisco Nualart ^1 2, Manuel Cifuentes ³, Eder Ramírez ², Fernando Martínez ¹, María José Barahona ², Luciano Ferrada ², Natalia Saldivia ¹, Ernesto R Bongarzone ⁴, Bernard Thorens ⁵, Katterine Salazar ¹

Abstract

Hyperglycemia increases glucose concentrations in the cerebrospinal fluid (CSF), activating glucose-sensing mechanisms and feeding behavior in the hypothalamus. Here, we discuss how hyperglycemia temporarily modifies ependymal cell ciliary beating to increase hypothalamic glucose sensing. A high level of glucose in the rat CSF stimulates glucose transporter 2 (GLUT2)-positive subcommissural organ (SCO) cells to release SCO-spondin into the dorsal third ventricle. Genetic inactivation of mice GLUT2 decreases hyperglycemia-induced SCO-spondin secretion. In addition, SCO cells secrete Wnt5a-positive vesicles; thus, Wnt5a and SCO-spondin are found at the apex of dorsal ependymal cilia to regulate ciliary beating. Frizzled-2 and ROR2 receptors, as well as specific proteoglycans, such as glypican/testican (essential for the interaction of Wnt5a with its receptors) and Cx43 coupling, were also analyzed in ependymal cells. Finally, we propose that the SCO-spondin/Wnt5a/Frizzled-2/Cx43 axis in ependymal cells regulates ciliary beating, a cyclic and adaptive signaling mechanism to control glucose sensing.

• PMID: 37733692
• PMCID: PMC10513282
• DOI: 10.1371/journal.pbio.3002308

Cell Rep Med. 2023 Aug 15;4(8):101155.
doi: 10.1016/j.xcrm.2023.101155.

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease

Ruth Hanssen ¹, Chiara Auwerx ², Maarja Jõeloo ³, Marie C Sadler ⁴; Estonian Biobank Research Team ⁵; Elana Henning ¹, Julia Keogh ¹, Rebecca Bounds ¹, Miriam Smith ¹, Helen V Firth ⁶, Zoltán Kutalik ⁴, I Sadaf Farooqi ⁷, Alexandre Reymond ⁸, Katherine Lawler ⁹

Abstract

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10^-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10^-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

• PMID: 37586323
• PMCID: PMC10439272
• DOI: 10.1016/j.xcrm.2023.101155

Biol Open. 2023 May 15;12(5):bio059783.

 doi: 10.1242/bio.059783. Epub 2023 May 17.

Actin filaments accumulated in the nucleus remain in the vicinity of condensing chromosomes in the zebrafish early embryo

Haruka Oda ¹, Yuko Sato ¹, Shigehiro A Kawashima ², Yusuke Fujiwara ², Máté Pálfy ³, Edlyn Wu ^3 4, Nadine L Vastenhouw ^3 4, Motomu Kanai ², Hiroshi Kimura ¹

Abstract

In the cytoplasm, filamentous actin (F-actin) plays a critical role in cell regulation, including cell migration, stress fiber formation, and cytokinesis. Recent studies have shown that actin filaments that form in the nucleus are associated with diverse functions. Here, using live imaging of an F-actin-specific probe, superfolder GFP-tagged utrophin (UtrCH-sfGFP), we demonstrated the dynamics of nuclear actin in zebrafish (Danio rerio) embryos. In early zebrafish embryos up to around the high stage, UtrCH-sfGFP increasingly accumulated in nuclei during the interphase and reached a peak during the prophase. After nuclear envelope breakdown (NEBD), patches of UtrCH-sfGFP remained in the vicinity of condensing chromosomes during the prometaphase to metaphase. When zygotic transcription was inhibited by injecting α-amanitin, the nuclear accumulation of UtrCH-sfGFP was still observed at the sphere and dome stages, suggesting that zygotic transcription may induce a decrease in nuclear F-actin. The accumulation of F-actin in nuclei may contribute to proper mitotic progression of large cells with rapid cell cycles in zebrafish early embryos, by assisting in NEBD, chromosome congression, and/or spindle assembly.

• PMID: 37071022
• PMCID: PMC10214854
• DOI: 10.1242/bio.059783

Nature. 2023 Jul 17.

 doi: 10.1038/d41586-023-01618-5. Online ahead of print.

Sleeping embryonic genomes are awoken by OBOX proteins

Edlyn Wu, Nadine L Vastenhouw

Activation of gene transcription is precisely regulated in early embryos. The identification of key transcription factors now shows how the transcription machinery is guided to the right place at the right time in mice.

Keywords: Developmental biology; Molecular biology.

• PMID: 37460688
• DOI: 10.1038/d41586-023-01618-5

Trends Plant Sci. 2023 Aug 11;S1360-1385(23)00232-7.

 doi: 10.1016/j.tplants.2023.07.001. Online ahead of print.

25 Years of thermomorphogenesis research: milestones and perspectives

Marcel Quint ¹, Carolin Delker ², Sureshkumar Balasubramanian ³, Martin Balcerowicz ⁴, Jorge J Casal ⁵, Christian Danve M Castroverde ⁶, Meng Chen ⁷, Xuemei Chen ⁸, Ive De Smet ⁹, Christian Fankhauser ¹⁰, Keara A Franklin ¹¹, Karen J Halliday ¹², Scott Hayes ¹³, Danhua Jiang ¹⁴, Jae-Hoon Jung ¹⁵, Eirini Kaiserli ¹⁶, S Vinod Kumar ¹⁷, Daniel Maag ¹⁸, Eunkyoo Oh ¹⁹, Chung-Mo Park ²⁰, Steven Penfield ²¹, Giorgio Perrella ²², Salomé Prat ²³, Rodrigo S Reis ²⁴, Philip A Wigge ²⁵, Björn C Willige ²⁶, Martijn van Zanten ²⁷

Abstract

In 1998, Bill Gray and colleagues showed that warm temperatures trigger arabidopsis hypocotyl elongation in an auxin-dependent manner. This laid the foundation for a vibrant research discipline. With several active members of the ‘thermomorphogenesis’ community, we here reflect on 25 years of elevated ambient temperature research and look to the future.

Keywords: high temperature signalling; hypocotyl; phytohormones; thermomorphogenesis; thermosensor.

• PMID: 37574427
• DOI: 10.1016/j.tplants.2023.07.001