The hypoxia signaling pathway and hypoxic adaptation in fishes

XIAO Wuhan 0 1 0 hypoxia , hypoxia-inducible factors, PHDs, pVHL, FIH, fish 1 Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences , Wuhan 430072 , China The hypoxia signaling pathway is an evolutionarily conserved cellular signaling pathway present in animals ranging from Caenorhabditis elegans to mammals. The pathway is crucial for oxygen homeostasis maintenance. Hypoxia-inducible factors (HIF-1 and HIF-2) are master regulators in the hypoxia signaling pathway. Oxygen concentrations vary a lot in the aquatic environment. To deal with this, fishes have adapted and developed varying strategies for living in hypoxic conditions. Investigations into the strategies and mechanisms of hypoxia adaptation in fishes will allow us to understand fish speciation and breed hypoxia-tolerant fish species/strains. This review summarizes the process of the hypoxia signaling pathway and its regulation, as well as the mechanism of hypoxia adaptation in fishes. - Approximately 2.5 billion years ago, photosynthesis led to the accumulation of oxygen to levels that were likely toxic to many obligate anaerobes. However, increased availability of atmospheric O2 led to the evolution of an extraordinarily efficient system of oxidative phosphorylation. In this system, chemical energy stored in the carbon bonds of organic molecules is transferred to the high-energy phosphate bond in ATP, which is then used to power physicochemical reactions in living cells [1]. Additionally, O2 serves as the final electron acceptor in oxidative phosphorylation, which is not only required for energy production, but is also the direct substrate of many enzymes. Thus, it is critical for the growth, development, and reproduction of organisms. Consequently, metazoans have evolved complicated systems of cellular metabolism and physiology to maintain oxygen homeostasis and have developed a biochemical response to low oxygen levels [2]. There are a number of oxygen-sensing pathways that promote hypoxia tolerance by activating transcription and inhibiting translation: the energy and nutrient sensor mTOR, the unfolded protein response that activates the endoplasmic stress response, and the nuclear factor (NF)-B transcriptional response [3]. However, hypoxia-inducible factors (HIFs) are recognized as master regulators of the cellular response to hypoxic stress [4,5]. The hypoxia signaling pathway is evolutionarily conserved from Caenorhabditis elegans to human beings and it activates similar or homogenous gene expression, resulting in similar physical and biochemical responses. Compared with the terrestrial environment, oxygen concentrations vary greatly in the aquatic environment [6]. Thus, compared with most birds and mammals, fishes are tolerant of this varying oxygen availability. Natural selection by oxygen concentration has facilitated the evolution of fishes with a range of adaptations to variable oxygen concentration. Even in waters at the same latitude, closely related species or different strains within a species exhibit varied adaptations to oxygen concentration. Additionally, closely related fishes distributed in waters at different latitudes exhibit extensive variation in their tolerance of hypoxia. Determining the mechanisms of hypoxia adaptation in fishes will not only help us to un The Author(s) 2015. This article is published with open access at link.springer.com derstand fish speciation and the evolution of the hypoxia signaling pathway, but will also guide us in the breeding of hypoxia-tolerant fish species/strains. 1 HIF and the regulation of the hypoxia signaling pathway HIF is a master regulator in the hypoxia signaling pathway and is expressed by all extant metazoan species analyzed to date. HIF is a heterodimer comprising an oxygen-labile -subunit (HIF-) and a constitutively expressed -subunit (HIF- or ARNT). Each unit contains the basic helix-loop-helix-PAS (bHLH-PAS) domains, which mediate the formation of heterodimers and DNA binding. HIF- dimerizes with other bHLH-PAS proteins and is stably expressed, but HIF- determines HIF-1 transcriptional activity [1,4,7]. Under normoxia (normal oxygen tension), either HIF-1 or HIF-2 is hydroxylated on specific conserved proline residues by prolyl-hydroxylase domains (PHDs), which contain enzymes (including PHD1, PHD2, and PHD3; PHD2 is thought to be essential), using molecular oxygen as a substrate [8]. In the reaction, one oxygen atom is inserted into the prolyl residue; a second atom is inserted into the co-substrate -ketoglutarate, splitting it into CO2 and succinate. Hydroxy-HIF- is recognized by von Hippel-Lindau tumor suppressor protein (pVHL) and is subsequently ubiquitylated by the VBC ubiquitin-ligase complex, marking HIF- for degradation by the 26S proteasome [9]. However, under hypoxic conditions, PHD catalytic activity is inhibited by the lack of oxygen and HIF- is not hydroxylated, thus, HIF- is not recognized by the VBC complex, allowing HIF- to stabilize. Stable HIF- is transferred into the nucleus and heterodimerizes with stable HIF-1. HIF heterodimers recognize and bind to hypoxia response elements (HREs) in the genome with the consensus sequence G/ACGTG to regulate the transcription of genes together with co-activators such as CBP/p300, resulting in a series of physical and biochemical responses (Figure 1) [1,4]. Because HIF- plays such an important role in the hypoxia signaling pathway, HIF- modulation is assumed to be a major mechanism for the regulation of the hypoxia signaling pathway. HIF- modulation includes transcription regulation and post translation modulation (PTM). At present, there are few reports on HIF- transcription regulation. Those available mainly focus on post translation HIF- modulation. NF-B activates HIF-1 expression, linking innate immunity to the hypoxic response [10]. HIF- PTM is exhibited in many pathways. Apart from VHL-mediated HIF- proteasomal degradation, HIF- is modulated by acetylation/deacetylation, phosphorylation/de-phosphorylation [11], sumoylation, and neddylation [12]. Histone acetyltransferase p300/CBP enhances HIF-1 transcriptional activity by interacting with the HIF-1 C-terminus [13]. Figure 1 Hypoxia signaling pathway. NAD+ dependent-deacetylase, Sirt1, Sirt3, Sirt6, and Sirt7 regulate HIF- activity either positively or negatively, playing important roles in cell metabolism, life span, tumorigenesis, and cardiovascular disease [1421]. As reported by Shao et al. [22] hypoxia stimulates an increase in mRNA and SUMO-1 protein levels. SUMO-1 co-localize with HIF-1 in the nucleus to induce HIF-1 sumoylation, resulting in the stabilization and enhancement of HIF-1 transcriptional activity [2224]. Furthermore, even though some HIF-1 and HIF-2 interacting proteins cannot modify HIF-1 and HIF-2, they can regulate their stability and transcriptional activity either positively or negatively via specific mechanisms. PKM2 enhances HIF-1 tran (...truncated)