Lessons from Comparison of Hypoxia Signaling in Plants and Mammals

Abstract

Hypoxia is an important stress for organisms, including plants and mammals. In plants, hypoxia can be the consequence of flooding and causes important crop losses worldwide. In mammals, hypoxia stress may be the result of pathological conditions. Understanding the regulation of responses to hypoxia offers insights into novel approaches for crop improvement, particularly for the development of flooding-tolerant crops and for producing better therapeutics for hypoxia-related diseases such as inflammation and cancer. Despite their evolutionary distance, plants and mammals deploy strikingly similar mechanisms to sense and respond to the different aspects of hypoxia-related stress, including low oxygen levels and the resulting energy crisis, nutrient depletion, and oxidative stress. Over the last two decades, the ubiquitin/proteasome system and the ubiquitin-like protein SUMO have been identified as key regulators that act in concert to regulate core aspects of responses to hypoxia in plants and mammals. Here, we review ubiquitin and SUMO-dependent mechanisms underlying the regulation of hypoxia response in plants and mammals. By comparing and contrasting these mechanisms in plants and mammals, this review seeks to pinpoint conceptually similar mechanisms but also highlight future avenues of research at the junction between different fields of research.

Keywords: N-degron pathway; SUMO; hypoxia; mammals; nitric oxide; plants; ubiquitin/proteasome system.

Figure 1

Regulation of oxygen sensing and downstream signals in plants and mammals, with a focus on ubiquitination and sumoylation. Oxygen sensing is mediated by oxygen-dependent enzymes (PCOs in plants, and ADO, PHDs, and FIHs in mammals) that regulate cellular responses to oxygen (O₂) levels. These enzymes contribute to the regulation of the stability of transcription factors that act as master regulators of hypoxia response genes (i.e., ERF-VIIs in plants and HIF1α in mammals). Oxidation of N-terminal cysteine residues by PCOs and ADO (in plants and mammals, respectively) results in the degradation of target proteins via the evolutionarily conserved N-degron pathway. In plants, this includes the ERF-VII transcription factors, following their arginylation by ATE enzymes and ubiquitination by the E3 ubiquitin ligase PRT6. In mammals, PHDs and FIHs hydroxylate specific proline and asparagine residues, respectively, on HIF1α, which can then be ubiquitinated by the E3 ubiquitin ligase VHL. A conserved group of E3 ubiquitin ligases, SINAT1/2 in plants and SIAH1a/2 in mammals, also regulate the stability of hypoxia master regulators in plants and mammals. Sumoylation is involved in the regulation of HIF1α; however, there are conflicting reports on its effect on HIF1α.

Figure 2

Regulation of NO production and effects of NO on hypoxia sensing and response. In plants, NR catalyzes the first step of NO biosynthesis turning nitrate into nitrite. Nitrite can then be reduced to NO by NR, NI-NOR, XOR, and complexes III and IV of the mitochondrial electron transport chain. The latter results from the use of nitrite as a terminal electron acceptor (i.e., the nitrite-phytoglobin (PGB) cycle). In mammals, eNOS produces NO via oxidative or reductive mechanisms depending on the oxygen level. XOR is also capable of reducing nitrite to NO, as is complex III of the mitochondrial electron transport chain. NR and eNOS activity and their stability are regulated directly and indirectly by phosphorylation and ubiquitination. NR is also regulated by SUMO. In both plants and mammals, the N-degron pathway acts as a sensor of NO. In mammals, NO also affects the HIF-dependent oxygen-sensing pathway. Solid lines: confirmed pathways/interactions; dashed lines: proposed pathways/interactions.