The methyltransferase SMYD3 regulates a new function of hypoxic tolerance in the body

Oxygen affects the physiological activity
of the animal organism through a variety of mechanisms.
Insufficient oxygen supply (hypoxia) can lead to dysfunction and even apoptosis
of the body's cells.
During the evolution of animals, unique molecular mechanisms for sensing and adapting to oxygen changes have been developed, among which hypoxia-signaling mediated by hypoxia-inducible factor (HIF) is crucial
.
Under aerobic conditions, proline hydroxylase PHDs use_O2 as a cofactor hydroxylation to modify the hypoxia-inducible factor HIF-α, resulting in HIF-α being recognized by the E3 ubiquitin ligase complex formed by pVHL and others, and then rapidly degraded by proteasomes.
Under hypoxic conditions, due to the lack of oxygen, the activity of proline hydroxylase PHDs is inhibited, HIF-α cannot undergo hydroxylation modification, resulting in its ubiquitination degradation pathway is blocked, HIF-α can accumulate, enter the nucleus, form a complex with HIF-1β, regulate the expression of hypoxia downstream genes and the body's hypoxic stress response
.
Identifying and resolving the regulators of hypoxic signaling pathways will help us understand the mechanisms
of hypoxic adaptation and hypoxic tolerance in the body.

Recently, Xiao Wuhan's team from the Institute of Hydrobiology, Chinese Academy of Sciences revealed the mechanism by which methyltransferase SMYD3 inhibits hypoxic tolerance by activating the hypoxia signaling pathway, and this inhibitory function does not depend on the methyltransferase activity
of SMYD3.

In this study, the results of overexpression and knockout experiments showed that SMYD3 could activate the hypoxia signaling pathway, and this effect did not depend on the most classical regulatory mode of HIF-α, namely PHDs-mediated hydroxylation modification and pVHL-mediated ubiquitination modification
.
The results of co-immunoprecipitation and immunofluorescence experiments showed that SMYD3 could directly bind to and stabilize HIF-α, which led to increased HIF-α in the nucleus and enhanced the expression of downstream genes of HIF-α, but this effect did not depend on the methyltransferase activity
of SMYD3.

In vitro and in vivo to further reveal the molecular mechanism
by which SMYD3 regulates the hypoxia signaling pathway.
At the cellular level, SMYD3 promotes apoptosis
by activating hypoxic signaling pathways that induce reactive oxygen species (ROS) accumulation.
In individual water bodies, smyd3-knocked zebrafish can significantly enhance hypoxic tolerance
.

This research work not only reveals the biological function and mechanism of SMYD3 in hypoxic tolerance in the body, but also provides a potential molecular target for the cultivation of new species of
hypoxia-tolerant fish.

The study, titled Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity, was published online in the Journal of Biological Chemistry
。 Researcher Xiao Wuhan and Associate Researcher Liu Xing of the Institute of Aquatic Sciences are the corresponding authors of the paper, and Wang Zixuan, a doctoral student, is the first author
of the paper.
The research was supported
by the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, and the National Key Research and Development Program.

Link to paper: https://doi.
org/10.
1016/j.
jbc.
2022.
102633

Hypoxia specifically inhibits the expression of methyltransferase SMYD3

Knockout of SMYD3 enhances hypoxic tolerance in zebrafish

Diagram of the mode of action of SMYD3 in regulating hypoxic response