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Discover the secret of hypoxia tolerance in fish

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By Milthon Lujan

HIF-1α can stabilize its protein through K63-linked polyubiquitination under hypoxia, stabilized HIF1α proteins dimerize with HIF1β proteins, translocate to the nucleus, and induce transcription of genes involved in adaptation or tolerance to hypoxia. USP3 deubiquitinates K63-linked polyubiquitination of HIF-1α to induce HIF-1α degradation and suppress hypoxia signaling. Credit: J. Li et al
HIF-1α can stabilize its protein through K63-linked polyubiquitination under hypoxia, stabilized HIF1α proteins dimerize with HIF1β proteins, translocate to the nucleus, and induce transcription of genes involved in adaptation or tolerance to hypoxia. USP3 deubiquitinates K63-linked polyubiquitination of HIF-1α to induce HIF-1α degradation and suppress hypoxia signaling. Credit: J. Li et al

Oxygen is an essential element for survival. Ocean warming, circadian rhythm, eutrophication, high-density aquaculture, power outages, and live fish transport can lead to low oxygen levels in water. This oxygen reduction can affect the health of aquatic animals, potentially causing ecological damage or economic losses.

The concentration of dissolved oxygen in water significantly impacts fish survival, development, growth, and population structure. It is a key environmental factor determining the success of aquaculture. The hypoxia signaling pathway mediated by hypoxia-inducible factor (HIF) plays a crucial role in influencing adaptation and tolerance to hypoxia (insufficient oxygen).

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Understanding the complexities of this regulation reveals valuable information about how organisms adapt to and tolerate hypoxic conditions. A study by scientists from the Institute of Hydrobiology, Hubei Hongshan Laboratory, the University of Chinese Academy of Sciences, and The Innovation of Seed Design sheds light on a key player in this biological symphony: ubiquitin-specific protease 3 (Usp3) in zebrafish.

PHD Activity

Under hypoxic conditions, the activity of prolyl hydroxylases (PHD) decreases, leading to the stabilization and accumulation of HIFα proteins. Stabilized HIFα proteins dimerize with HIF1β proteins, translocate to the nucleus, and induce the transcription of genes involved in adaptation or tolerance to hypoxia.

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Factors influencing the hypoxia signaling pathway mainly affect the stability of HIFα protein. Therefore, identifying and analyzing regulators of the hypoxia signaling pathway will help us understand the mechanism of adaptation to hypoxia and hypoxia tolerance in fish.

The Role of Ubiquitin

Recently, a team of researchers in China discovered that the absence of ubiquitin-specific protease 3 (usp3) significantly improved the hypoxic capacity of zebrafish and revealed the usp3 mechanism by inhibiting hypoxic signaling and hypoxic tolerance in zebrafish.

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The team’s findings, published in the Water Biology and Security journal, revealed a new function of usp3 to influence hypoxia signaling and showed that tusp3-mediated degradation of HIF-1α alters hypoxia signaling, leading to a decrease in hypoxia tolerance.

Scientists found that Usp3 specifically binds to hif-1αa, inducing its proteasomal degradation through its deubiquitinase activity. This unique process results in the suppression of hypoxia signaling under low oxygen conditions.

“We found that the absence of ubiquitin-specific protease 3 (usp3) in zebrafish enhances hypoxia tolerance,” says Wuhan Xiao, corresponding co-author of the study. “Specifically, zebrafish usp3 exclusively binds to HIF-1αa and triggers its proteasomal degradation, a process dependent on its deubiquitinase activity. This mechanism results in the attenuation of hypoxia signaling during hypoxic conditions.”

Additionally, usp3 facilitates the deubiquitination of K63 polyubiquitinated HIF-1αa. Endogenous evidence supports that mammalian USP3 reflects the regulatory role of zebrafish USP3 in modulating HIF-1α activity.

Implications and Future Perspectives

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The discovery of Usp3’s involvement in hypoxia tolerance opens a new chapter in our understanding of oxygen homeostasis. By deciphering the mechanisms through which Usp3 influences the HIF-mediated hypoxia signaling pathway, researchers gain valuable insights into potential therapeutic strategies for conditions involving oxygen deprivation.

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Conclusion

“In this study, we report that under hypoxia, zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation, leading to the suppression of hypoxia signaling. Using an in vivo model, we found that the loss of usp3 promotes hypoxia tolerance in zebrafish,” the researchers concluded.

As researchers unravel the intricate mechanisms through which Usp3 influences HIF-1α degradation, the potential for therapeutic interventions in hypoxia-related conditions becomes increasingly promising.

This study marks a significant step in understanding the molecular nuances of hypoxia tolerance, with Usp3 taking a central role.

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The study was funded by NSFC and The Strategic Priority Research Program of the Chinese Academy of Sciences.

Contact
Wuhan Xiao
Institute of Hydrobiology
Chinese Academy of. Sciences, PR China.
Email: w-xiao@ihb.ac.cn

Jing Wang
Wuhan Xiao
Institute of Hydrobiology
Chinese Academy of. Sciences, PR China.
Email: wangjing@ihb.ac.cn

Reference (open access)
Li, J., Zhou, Z., Cai, X., Song, Y., Li, Z., Li, Z., … & Wang, J. (2024). Zebrafish usp3 loss promotes hypoxic tolerance by disrupting deubiquitination of K63-polyubiquitinated hif-1αa. Water Biology and Security, 100245.