Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice

Xin Zhang, Can Hu, Zhen-Guo Ma, Min Hu, Xiao-Pin Yuan, Yu-Pei Yuan, Sha-Sha Wang, Chun-Yan Kong, Teng Teng and Qi-Zhu Tang ()
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Xin Zhang: Hubei Key Laboratory of Metabolic and Chronic Diseases
Can Hu: Hubei Key Laboratory of Metabolic and Chronic Diseases
Zhen-Guo Ma: Hubei Key Laboratory of Metabolic and Chronic Diseases
Min Hu: Hubei Key Laboratory of Metabolic and Chronic Diseases
Xiao-Pin Yuan: Hubei Key Laboratory of Metabolic and Chronic Diseases
Yu-Pei Yuan: Hubei Key Laboratory of Metabolic and Chronic Diseases
Sha-Sha Wang: Hubei Key Laboratory of Metabolic and Chronic Diseases
Chun-Yan Kong: Hubei Key Laboratory of Metabolic and Chronic Diseases
Teng Teng: Hubei Key Laboratory of Metabolic and Chronic Diseases
Qi-Zhu Tang: Hubei Key Laboratory of Metabolic and Chronic Diseases

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.

Date: 2023
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DOI: 10.1038/s41467-023-39159-0

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