CRISPR screens reveal ZBTB17/MIZ1 as a peroxisome regulator DOI
Hongqin Liu, Xi Chen, Hanlin Wang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 26, 2024

ABSTRACT Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes humans, with defects often linked to diseases. The functions of peroxisomes regulated at transcriptional, translational, post-translational levels. In this study, we employed the CRISPR/Cas9-based genetic screening a ubiquitin ligase library identify regulators human peroxisomes. We discovered that ZBTB17 (also referred as MIZ1) plays role regulating import proteins into Independent its activity, ZBTB17/MIZ1 operates transcription factor directly modulate expression key importer PEX13, thereby influencing localization peroxisomal enzymes. Furthermore, metabolomic profiling reveals knockdown or PEX13 results similar alterations, characterized by downregulated purine synthesis, suggesting ZBTB17’s regulation likely through Collectively, regulator protein import, affecting function nucleotide metabolism. Our findings provide insights multifaceted complex cells shed light on molecular mechanisms underlying transcriptional regulator.

Язык: Английский

PEX1G843D remains functional in peroxisome biogenesis but is rapidly degraded by the proteasome DOI Creative Commons
Connor J. Sheedy, Soham P. Chowdhury, Bashir A. Ali

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер unknown, С. 108467 - 108467

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
ZBTB17/MIZ1 promotes peroxisome biogenesis by transcriptional regulation of PEX13 DOI Creative Commons
Hongqin Liu, Xi Chen, Hanlin Wang

и другие.

The Journal of Cell Biology, Год журнала: 2025, Номер 224(6)

Опубликована: Апрель 17, 2025

Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes humans, with defects linked to diseases. The functions of peroxisomes regulated at transcriptional, translational, posttranslational levels. In this study, we employed the CRISPR/Cas9-based screening a ubiquitin ligase library identify regulators human peroxisomes. We discovered that ZBTB17 (MIZ1) plays role regulating import proteins into Independent its activity, ZBTB17/MIZ1 operates as transcription factor modulate expression key importer PEX13, influencing localization peroxisomal enzymes. Furthermore, metabolomic profiling reveals knockdown or PEX13 results similar alterations, downregulated purine synthesis. Collectively, regulator protein import, thereby affecting function nucleotide metabolism. Our findings provide insights multifaceted regulation complex cells shed light on molecular mechanisms underlying ZBTB17’s transcriptional regulator.

Язык: Английский

Процитировано

0
PEX1G843D remains functional in peroxisome biogenesis but is rapidly degraded by the proteasome DOI Creative Commons
Connor J. Sheedy, Soham P. Chowdhury, Bashir A. Ali

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 13, 2024

Abstract The PEX1/PEX6 AAA-ATPase is required for the biogenesis and maintenance of peroxisomes. Mutations in HsPEX1 HsPEX6 disrupt peroxisomal matrix protein import are leading cause Peroxisome Biogenesis Disorders (PBDs). most common disease-causing mutation PEX1 Hs G843D allele, which results a reduction import. Here we demonstrate that vitro homologous yeast mutant, Sc Pex1 G700D , reduces stability Pex1’s active D2 ATPase domain impairs assembly with Pex6, but can still form an motor. In vivo exhibits only slight defect peroxisome We generated model human cell lines show rapidly degraded by proteasome, induced overexpression restore Additionally, found PEX1’s affinity PEX6, impaired sufficient to induce degradation WT . Lastly, fusing deubiquitinase significantly hinders its mammalian cells. Altogether, our findings suggest novel regulatory mechanism hexamer highlight potential stabilization as therapeutic strategy PBDs arising from other hypomorphs.

Язык: Английский

Процитировано

1
FAF2 is a bifunctional regulator of peroxisomal homeostasis and saturated lipid responses DOI Creative Commons
Choah Kim, Katlyn R. Gabriel,

Dylan Boone

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 17, 2024

Abstract Exposure to saturated fatty acids (SFAs), such as palmitic acid, can lead cellular metabolic dysfunction known lipotoxicity. Although canonical adaptive processes like lipid storage or desaturation are responses fat exposure, the link between SFA metabolism and organellar biology remains an area of active inquiry. We performed a genome-wide CRISPR knockout screen in human epithelial cells identify modulators toxicity. The revealed peroxisomal proteins, especially those that impact ether synthesis, important regulators identified Fas-associated factor family member 2 (FAF2) critical bifunctional co-regulator acid biology. further uncovered new biological function for ubiquitin-regulatory X (UBX) UAS thioredoxin-like domains FAF2, demonstrating their requirement protein abundance SFA-induced stress. Our work highlights role FAF2 regulating function, peroxisome key organelle response SFAs.

Язык: Английский

Процитировано

1
CRISPR screens reveal ZBTB17/MIZ1 as a peroxisome regulator DOI
Hongqin Liu, Xi Chen, Hanlin Wang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 26, 2024

ABSTRACT Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes humans, with defects often linked to diseases. The functions of peroxisomes regulated at transcriptional, translational, post-translational levels. In this study, we employed the CRISPR/Cas9-based genetic screening a ubiquitin ligase library identify regulators human peroxisomes. We discovered that ZBTB17 (also referred as MIZ1) plays role regulating import proteins into Independent its activity, ZBTB17/MIZ1 operates transcription factor directly modulate expression key importer PEX13, thereby influencing localization peroxisomal enzymes. Furthermore, metabolomic profiling reveals knockdown or PEX13 results similar alterations, characterized by downregulated purine synthesis, suggesting ZBTB17’s regulation likely through Collectively, regulator protein import, affecting function nucleotide metabolism. Our findings provide insights multifaceted complex cells shed light on molecular mechanisms underlying transcriptional regulator.

Язык: Английский

Процитировано

0