Drosophila USP5 Controls the Activation of Apoptosis and the Jun N-Terminal Kinase Pathway during Eye Development

Fan, Xiaolan; Huang, Qinying; Ye, Xiaolei; Lin, Yi Wen; Chen, Yuting; Lin, Xinhua; Qu, Jia

doi:10.1371/journal.pone.0092250

Cited by 18 publications

(20 citation statements)

References 61 publications

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“…Consistent with allelic strength in different combinations of mutant alleles, the amounts of free polyubiquitin chains correlate with the animal lethal phases and tissue disorders. Meanwhile, loss of Drosophila USP5 has been shown to cause severe apoptosis in eye disks [23]. It is possible that small brain lobes and wing disks in close-to-null leon 1 /19-2 were due to severe apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development

Wang

Chen

Chien

2014

Biochemical and Biophysical Research Communications

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Ubiquitination and the reverse process deubiquitination regulate protein stability and function during animal development. The Drosophila USP5 homolog Leon functions as other family members of unconventional deubiquitinases, disassembling free, substrate-unconjugated polyubiquitin chains to replenish the pool of mono-ubiquitin, and maintaining cellular ubiquitin homeostasis. However, the significance of Leon/USP5 in animal development is still unexplored. In this study, we generated leon mutants to show that Leon is essential for animal viability and tissue integrity during development. Both free and substrate-conjugated polyubiquitin chains accumulate in leon mutants, suggesting that abnormal ubiquitin homeostasis caused tissue disorder and lethality in leon mutants. Further analysis of protein expression profiles in leon mutants shows that the levels of all proteasomal subunits were elevated. Also, proteasomal enzymatic activities were elevated in leon mutants. However, proteasomal degradation of ubiquitinated substrates was impaired. Thus, aberrant ubiquitin homeostasis in leon mutants disrupts normal proteasomal degradation, which is compensated by elevating the levels of proteasomal subunits and activities. Ultimately, the failure to fully compensate the dysfunctional proteasome in leon mutants leads to animal lethality and tissue disorder.

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Section: Discussionmentioning

confidence: 99%

The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development

Wang

Chen

Chien

2014

Biochemical and Biophysical Research Communications

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“…We previously reported that Usp5 is required for Drosophila photoreceptor development and to investigate the underlying mechanism further, we examined signaling pathways critical for photoreceptor development. One of our candidate pathways is Notch signaling, which plays an important role in the specification of photoreceptors .…”

Section: Resultsmentioning

confidence: 99%

“…All Fly stocks were maintained at 25 °C on standard condition. The Usp5 mutant flies Usp5m/TM6B (the Usp5 9 mutant allele) were generated by P‐element hopping as described previously . ywflp; M(3)65FhsGFPFRT2A/TM6B , hs‐flp; tubGal4UASGFP/cyo; tub‐Gal80FRT2A/TM6B , E(spl)m8‐lacZ , UAS‐NotchRNAi (BL28981), and ywflp; Act>y+>Gal4,UAS‐GFP were obtained from Bloomington Drosophila Stock Center (Department of Biology, Indiana University, Bloomington, IN, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, discs were washed in PBST (0.1% Triton X‐100 in PBS) and blocked in 5% BSA for 15 min, followed by incubation with antibodies. The primary antibodies used in this experiment were: Mouse anti‐NICD (dilution 1 : 100; DSHB, Iowa City, IA, USA); Mouse anti‐NECD (dilution 1 : 50; DSHB); Goat anti‐Su(H) (dilution 1 : 50; Santa Cruz Biotechnology, Santa Cruz, CA, USA); Chicken anti‐β‐Gal (dilution 1 : 1000; Abcam, Cambridge, MA, USA); Mouse anti‐Argos (dilution 1 : 50; DHSBP; Mouse anti‐Yan (dilution 1 : 50; DSHB); Rabbit anti‐dpERK (dilution 1 : 50; Cell Signaling Technology, Beverly, MA, USA); Goat anti‐EGFR (dilution 1 : 50; Santa Cruz Biotechnology); Goat anti‐Sev (dilution 1 : 50; Santa Cruz Biotechnology); and Mouse anti‐Usp5 (dilution 1 : 800; made in our laboratory) . Images were captured using an LSM780 Confocal Laser Scanning System (Carl Zeiss, Oberkochen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that the loss of Usp5 reduced the number of photoreceptors, including R8, R3, R4 and cone cells . However, other functions of Usp5 during Drosophila eye development and the mechanism how Usp5 regulates different signaling pathways for photoreceptor differentiation are still largely unknown.…”

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confidence: 99%

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The deubiquitinating enzyme Usp5 regulates Notch and RTK signaling during Drosophila eye development

Ling

Huang

et al. 2017

FEBS Letters

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Usp5 belongs to the USP family of deubiquitinating enzymes (DUBs), which comprises the largest class of DUBs. We previously reported that loss of Usp5 impairs development of photoreceptors in Drosophila eyes, although the detailed mechanism remained unclear. In the present study, we demonstrate that Usp5 regulates both Notch and receptor tyrosine kinase (RTK) signaling. Loss of Usp5 results in upregulation of Notch signaling and downregulation of RTK signaling, leading to impaired photoreceptor development. Moreover, genetic rescue experiments with the DNA binding protein Suppressor of Hairless or Notch RNAi indicate that they mediate the regulation of RTK signaling by Usp5. The present study provides mechanistic insight into how Usp5 regulates photoreceptor differentiation by Notch and RTK signaling in the Drosophila eye.

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The ubiquitin‐specific protease 5 mediated deubiquitination of LSH links metabolic regulation of ferroptosis to hepatocellular carcinoma progression

Yan

Guo

Wang

et al. 2023

MedComm

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Epigenetic regulators and posttranslational modifications of proteins play important roles in various kinds of cancer cell death, including ferroptosis, a non‐apoptotic form of cell death. However, the interplay of chromatin modifiers and deubiquitinase (DUB) in ferroptosis remains unclear. Here, we found that ubiquitin‐specific protease 5 (USP5) is regarded as a bona fide DUB of lymphoid‐specific helicase (LSH), a DNA methylation repressor, in hepatocellular carcinoma (HCC). Functional studies reveal that USP5 interacts with LSH and stabilizes LSH by a deubiquitylation activity‐dependent process. Furthermore, the USP5‐mediated deubiquitination of LSH facilitates the tumorigenesis of HCC by upregulating solute carrier family 7 member 11 (SLC7A11) to suppress ferroptosis of liver cancer cells. Moreover, the USP5 inhibitor degrasyn inhibits DUB activities of USP5 to LSH to suppress the progression of HCC. Additionally, USP5 and LSH are positively correlated and both are overexpressed and linked to poor prognosis in HCC patients. Together, our findings show that USP5 interacts with LSH directly and enhances LSH protein stability through deubiquitination, which, in turn, promotes the development of HCC by suppressing ferroptosis of liver cancer cells, suggesting that USP5 may be a potential therapeutic target for HCC.

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Drosophila USP5 Controls the Activation of Apoptosis and the Jun N-Terminal Kinase Pathway during Eye Development

Cited by 18 publications

References 61 publications

The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development

The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development

The deubiquitinating enzyme Usp5 regulates Notch and RTK signaling during Drosophila eye development

The ubiquitin‐specific protease 5 mediated deubiquitination of LSH links metabolic regulation of ferroptosis to hepatocellular carcinoma progression

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