Liu Ying, Feng Xuhui, Wu Han, Gui Tianxiang, Fu Mingfeng, Luo Xudong, Zhao Lei, Chen Li-Ming
Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science & Technology, Huazhong University of Science & Technology, 1037 Luoyu Rd, Wuhan, 430074, Hubei, China.
Insitute of Biomedicine and Hubei Key Laboratory of Embryonic Stem Cell Research, College of Basic Medicine, Hubei University of Medicine, Shiyan, 442000, China.
Pflugers Arch. 2025 May 30. doi: 10.1007/s00424-025-03095-3.
IRBIT1 and IRBIT2 (collectively, the IRBITs) are signaling molecules with great universality in their expression (ubiquitous distribution in all major tissues in animals) and considerable versatility in their biological functions. Structurally, the IRBITs are highly homologous to S-adenosyl-L-homocysteine hydrolase (AHCY). However, the IRBITs had lost the catalytic activity during the evolution but gained new functions by the addition of a unique N-terminal IRBIT domain. By direct protein interaction, the IRBITs modulate the functions of an array of target proteins of distinct biological functions, ranging from membrane channels and transporters to cytosolic protein kinase, lipid kinases, ribonucleotide reductase, etc. The interaction of the IRBITs with specific target proteins is modulated by the redox couple NAD/NADH. The IRBITs are involved in the regulation of many cellular processes, such as Ca signaling, intracellular pH regulation, transepithelial transport of electrolytes and fluid, apoptosis, and DNA metabolism. However, what we have known about the IRBITs is likely just the tip of the iceberg. The present review covers the expression and distribution, physiological and pathological roles, and the structural organization of the IRBITs. It provides a comprehensive review on the binding partners of the IRBITs. Finally, the review addresses the evolution of the IRBITs in reference to the evolution of AHCY.
IRBIT1和IRBIT2（统称为IRBITs）是信号分子，其表达具有高度普遍性（在动物所有主要组织中广泛分布），生物学功能具有相当大的多样性。在结构上，IRBITs与S-腺苷-L-高半胱氨酸水解酶（AHCY）高度同源。然而，IRBITs在进化过程中失去了催化活性，但通过添加独特的N端IRBIT结构域获得了新功能。通过直接的蛋白质相互作用，IRBITs调节一系列具有不同生物学功能的靶蛋白的功能，从膜通道和转运蛋白到胞质蛋白激酶、脂质激酶、核糖核苷酸还原酶等。IRBITs与特定靶蛋白的相互作用受氧化还原对NAD/NADH的调节。IRBITs参与许多细胞过程的调节，如钙信号传导、细胞内pH调节、电解质和液体的跨上皮运输、细胞凋亡和DNA代谢。然而，我们对IRBITs的了解可能只是冰山一角。本综述涵盖了IRBITs的表达和分布、生理和病理作用以及结构组织。它对IRBITs的结合伙伴进行了全面综述。最后，本综述参照AHCY的进化探讨了IRBITs的进化。
