PUBLICATION

Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity

Authors

Wang, Z., Chen, X., Fan, S., Zhu, C., Deng, H., Tang, J., Sun, X., Jia, S., Liao, Q., Xiao, W., Liu, X.

ID

ZDB-PUB-221025-2

Date

2022

Source

The Journal of biological chemistry 298(12): 102633 (Journal)

Registered Authors

Xiao, Wuhan

Keywords

HIF1α, ROS, SMYD3, hypoxia signaling, hypoxia tolerance, zebrafish

MeSH Terms

Hypoxia-Inducible Factor 1, alpha Subunit/genetics
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Histone-Lysine N-Methyltransferase*/genetics
Histone-Lysine N-Methyltransferase*/metabolism
Von Hippel-Lindau Tumor Suppressor Protein/genetics
Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Methyltransferases*/metabolism
Zebrafish/metabolism
Hypoxia*/metabolism
Animals
Zebrafish Proteins*/genetics
Zebrafish Proteins*/metabolism
Signal Transduction

(all 13)

PubMed

36273580 Full text @ J. Biol. Chem.

Abstract

HIF1α, a main transcriptional regulator of the cellular response to hypoxia, also plays important roles in oxygen homeostasis of aerobic organisms, which is regulated by multiple mechanisms. However, the full cellular response to hypoxia has not been elucidated. In this study, we found that expression of SMYD3, a methyltransferase, augments hypoxia signaling independent of its enzymatic activity. We demonstrated SMYD3 binds to and stabilizes HIF1α via co-immunoprecipitation and Western blot assays, leading to the enhancement of HIF1α transcriptional activity under hypoxia conditions. In addition, the stabilization of HIF1α by SMYD3 is independent of HIF1α hydroxylation by prolyl hydroxylases (PHDs) and the intactness of the von Hippel-Lindau (VHL) ubiquitin ligase complex. Furthermore, we showed SMYD3 induces ROS accumulation and promotes hypoxia-induced cell apoptosis. Consistent with these results, we found smyd3-null zebrafish exhibit higher hypoxia tolerance compared to their wildtype siblings. Together, these findings define a novel role of SMYD3 in affecting hypoxia signaling and demonstrate that SMYD3-mediated HIF1α stabilization augments hypoxia signaling, leading to the impairment of hypoxia tolerance.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
egln3	smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism	RTPCR	Figure 10
egln3	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Figure 10
egln3	WT	hypoxia	Protruding-mouth	whole organism	RTPCR	Figure 10
pdk1	smyd3^{ihbsm3/ihbsm3}	standard conditions	Protruding-mouth	whole organism	RTPCR	Figure 10
pdk1	smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism	RTPCR	Figure 10
pdk1	WT	hypoxia	Protruding-mouth	whole organism	RTPCR	Figure 10
pdk1	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Figure 10
smyd3	smyd3^{ihbsm3/ihbsm3}	standard conditions	Protruding-mouth	whole organism	RTPCR	Figure 10
smyd3	WT	standard conditions	Protruding-mouth	whole organism	RTPCR	Figure 10
vegfaa	smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism	RTPCR	Figure 10

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	hypoxia	Protruding-mouth	whole organism egln3 expression increased amount, abnormal	Figure 10
WT	hypoxia	Protruding-mouth	whole organism pdk1 expression increased amount, abnormal	Figure 10
WT	hypoxia	Protruding-mouth	whole organism vegfaa expression increased amount, abnormal	Figure 10
WT	hypoxia	Adult	swimming behavior process quality, abnormal	Figure 10
WT	hypoxia	Adult	whole organism viability, abnormal	Figure 10
smyd3^{ihbsm3/ihbsm3}	standard conditions	Protruding-mouth	whole organism smyd3 expression decreased amount, abnormal	Figure 10
smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism egln3 expression amount, ameliorated	Figure 10
smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism pdk1 expression amount, ameliorated	Figure 10
smyd3^{ihbsm3/ihbsm3}	hypoxia	Protruding-mouth	whole organism vegfaa expression amount, ameliorated	Figure 10
smyd3^{ihbsm3/ihbsm3}	hypoxia	Adult	swimming behavior process quality, normal	Figure 10

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ihbsm3		Small Deletion	smyd3

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
smyd3	CRISPR1-smyd3	CRISPR

Fish

Fish
smyd3^{ihbsm3/ihbsm3}
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Wang et al., 2022 ZDB-PUB-221025-2 PMID:36273580

Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity

Wang et al., 2022

ZDB-PUB-221025-2
PMID:36273580