P4HB UFMylation regulates mitochondrial function and oxidative stress

Zhu, Jing; Ma, Xirui; Jing, Yu; Zhang, Guangya; Zhang, Dandan; Mao, Ziming; Ma, Xiaowen; Liu, Huifang; Chen, Fengling

doi:10.1016/j.freeradbiomed.2022.06.237

Cited by 22 publications

(24 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activating signal cointegrator 1 (ASC1) [44], P53 [42], Meiotic Recombination 11 Homolog 1 (MRE11) [51], Ribosomal Protein L26 (RPL26) [52], Ribophorin I (RPN1) [31], and Histone H4 [53], have been identi ed so far. Our latest research identi ed that P4HB is an ufmylation substrate which participates in regulating mitochondrial function damage, oxidative stress and ER stress [35]. Meanwhile, UFBP1 is the rstdiscovered substrate of ufmylation composed by a signal peptide, a nuclear localization signal, a DDRGK domain and a PCI domain.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of ufmylation modi cation system components are promoted by IRE1α/XBP1 branch, which is an adaptive response to ER stress [29,30]. De ciency of ufmylation results in severe ER stress [24,[31][32][33][34][35][36] and causes diseases including diabetes [24], ischemic heart disease [37], heart failure [34], hematologic diseases [38,39], atherosclerosis [40,41] and tumors [42,43]. UFM1 binding protein 1 (UFBP1) is the rst-discovered substrate of ufmylation and is required for further ufmylation of other substrates [44], which makes UFBP1 an pivotal factor in ufmylation.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous studies, ufmylation was proved to inhibit ER stress-induced apoptosis in macrophage cell [49] and suppress foam cell formation via promoting macrophage cholesterol e ux [41]. Recently, we identi ed Prolyl 4-Hydroxylase Subunit Beta (P4HB) as a new substrate of ufmylation and defective P4HB ufmylation caused mitochondrial function damage, oxidative stress, and ER stress in hepatocytes [35]. In this study, we identify an up-regulated ufmylation on proteins in livers with steatosis and provide evidences that UFBP1 plays an essential role in ameliorating NAFLD-related phenotypes through regulating hepatic ER stress in an ufmylation-dependent way, indicating ufmylation on UFBP1 is a potential target for NAFLD treatment.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Chen

Mao

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting NAFLD characteristics are limited. Ufmylation is a newly found post-translational modification in which the Ubiquitin-fold modifier 1 (UFM1) protein is attached to its substrate via ufmylation modification system components. Ufmylation has been proposed to regulate ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in the pathogenesis of NAFLD. However, the role of ufmylation in NAFLD is unknown. Herein, we aimed to reveal the role of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms. We observed an up-regulated expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models, which was an adaptive response to the hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 promoted lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by re-expressing exogenous wild type UFBP1 (WT UFBP1) but not an UFBP1 mutant deficient in main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in high fat diet (HFD)-induced NAFLD mice. We also demonstrated that knocking down UFBP1 promoted ER stress while re-expressing or overexpressing UFBP1 relieved ER stress in an ufmylation-dependent manner in NAFLD, which could be the underlying mechanism that led to the relief of abnormal hepatic lipogenesis and insulin resistance. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Chen

Mao

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Histone 4 is also UFMylated following DNA damage to maintain genomic integrity 16,17 . P53, P4HB, and ERα can all be UFMylated to antagonize degradation via the ubiquitin–proteasome pathway 10,18,19 …”

Section: Overview Of the Ufm1 Conjugation Systemmentioning

confidence: 99%

“…16,17 P53, P4HB, and ERα can all be UFMylated to antagonize degradation via the ubiquitin-proteasome pathway. 10,18,19 It has been proposed that most UFMylation components reside in the ER. UFL1, UFSP2, UFBP1, and CDK5RAP3 have all been shown to aggregate in a large protein complex at the cytosolic side of the ER membrane.…”

mentioning

confidence: 99%

The UFM1 conjugation system in mammalian development

Yang

Moy

Yang

2023

Developmental Dynamics

View full text Add to dashboard Cite

Posttranslational modifications by ubiquitin and ubiquitin‐like proteins are important in regulating cellular protein functions. UFM1 (ubiquitin‐fold modifier 1), first identified almost two decades ago, is a member of the ubiquitin‐like protein family. UFM1 is covalently conjugated to the target proteins in an enzymatic cascade consisting of E1 (activating), E2 (conjugating), and E3 (ligating) enzymes. At the molecular level, modification by UFM1 (UFMylation) is an important mediator of the protein function. Dysregulation of the UFM1 system, e.g., the knockout of UFMylation components, disturbs proteome homeostasis and triggers endoplasmic reticulum stress. Such changes are linked to developmental disorders, tumorigenesis, tissue injury, inflammation, and several hereditary neurological syndromes. This review will focus on the role of the UFMylation in animal development and associated congenital disorders. We will cover the hematopoietic system, liver, central nervous system, intestine, heart, kidney, immune, and skeletal system to provide insight into disease pathogenesis and shed light on possible novel therapeutic methods.

show abstract

Characterization of a silkworm UFM1 homolog in regulating Bombyx mori unfolded protein response and nucleopolyhedrovirus replication

Jiang

et al. 2023

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

P4HB UFMylation regulates mitochondrial function and oxidative stress

Cited by 22 publications

References 30 publications

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

The UFM1 conjugation system in mammalian development

Characterization of a silkworm UFM1 homolog in regulating Bombyx mori unfolded protein response and nucleopolyhedrovirus replication

Contact Info

Product

Resources

About