ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway

Yang, Yu-wei; Meng, Xiangyu; Meng, Yuanyuan; Tang, Haikang; Cheng, Ming-Hui; Zhang, Ziqi; Xu, Wenqing; Long, Wei

doi:10.1016/j.omtn.2021.05.008

Cited by 9 publications

(5 citation statements)

References 44 publications

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“…FIH may be part of the regulatory network connecting hypoxia and inflammation, as FIH alters IL-1β-induced NF-κB activity and is relevant for the inflammatory response in the gut in vivo . 12 , 14 , 15 Nonetheless, the extent of contribution of FIH activity to inflammation as well as the molecular mechanisms that connect FIH and inflammation are unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with the FIH-selective pharmacologic agent N-oxalyl-D-phenylalanine (NOFD) was protective against irradiation-induced injuries of the gastrointestinal tract and FIH deletion in the colon epithelium attenuated chronic colitis. 14 , 15 We previously demonstrated that the enzymatic activities of FIH and PHD1 attenuate the major pro-inflammatory IL-1β signaling pathway. 12 Nonetheless, the general relevance and the detailed FIH-dependent regulation of inflammation remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits

Volkova,

Jucht,

Oechsler

et al. 2024

Molecular and Cellular Biology

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Pharmacologic inhibitors of cellular hydroxylase oxygen sensors are protective in multiple preclinical in vivo models of inflammation. However, the molecular mechanisms underlying this regulation are only partly understood, preventing clinical translation. We previously proposed a new mechanism for cellular oxygen sensing: oxygen-dependent, (likely) covalent protein oligomer (oxomer) formation. Here, we report that the oxygen sensor factor inhibiting HIF (FIH) forms an oxomer with the NF-κB inhibitor β (IκBβ). The formation of this protein complex required FIH enzymatic activity and was prevented by pharmacologic inhibitors. Oxomer formation was highly hypoxia-sensitive and very stable. No other member of the IκB protein family formed an oxomer with FIH, demonstrating that FIH-IκBβ oxomer formation was highly selective. In contrast to the known FIH-dependent oxomer formation with the deubiquitinase OTUB1, FIH-IκBβ oxomer formation did not occur via an IκBβ asparagine residue, but depended on the amino acid sequence VAERR contained within a loop between IκBβ ankyrin repeat domains 2 and 3. Oxomer formation prevented IκBβ from binding to its primary interaction partners p65 and c-Rel, subunits of NF-κB, the master regulator of the cellular transcriptional response to pro-inflammatory stimuli. We therefore propose that FIH-mediated oxomer formation with IκBβ contributes to the hypoxia-dependent regulation of inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits

Volkova,

Jucht,

Oechsler

et al. 2024

Molecular and Cellular Biology

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“…Recently, the (to our knowledge) first use of NOFD was reported in animals. Repeated intraperitoneal injection of NOFD conferred radioprotection to the gastro-intestinal tract, which was suggested to be caused by increased HIF-1 transactivation activity (186). Analyzing the effect of 2-OG derivatives on FIH, 10 compounds were found to enhance FIH activity, whereas 17 compounds selectively inhibited FIH (118).…”

Section: Therapeutic Potential Of Pharmacologic Fih Inhibitionmentioning

confidence: 99%

The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor

Volkova

Jucht

Wenger

et al. 2022

Antioxidants & Redox Signaling

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Significance: Limited oxygen availability (hypoxia) commonly occurs in a range of physiological and pathophysiological conditions, including embryonic development, physical exercise, inflammation, and ischemia. It is thus vital for cells and tissues to monitor their local oxygen availability to be able to adjust in case the oxygen supply is decreased. The cellular oxygen sensor factor inhibiting hypoxiainducible factor (FIH) is the only known asparagine hydroxylase with hypoxia sensitivity. FIH uniquely combines oxygen and peroxide sensitivity, serving as an oxygen and oxidant sensor. Recent Advances: FIH was first discovered in the hypoxia-inducible factor (HIF) pathway as a modulator of HIF transactivation activity. Several other FIH substrates have now been identified outside the HIF pathway. Moreover, FIH enzymatic activity is highly promiscuous and not limited to asparagine hydroxylation. This includes the FIH-mediated catalysis of an oxygen-dependent stable (likely covalent) bond formation between FIH and selected substrate proteins (called oxomers [oxygen-dependent stable protein oligomers]). Critical Issues: The (patho-)physiological function of FIH is only beginning to be understood and appears to be complex. Selective pharmacologic inhibition of FIH over other oxygen sensors is possible, opening new avenues for therapeutic targeting of hypoxia-associated diseases, increasing the interest in its (patho-)physiological relevance. Future Directions: The contribution of FIH enzymatic activity to disease development and progression should be analyzed in more detail, including the assessment of underlying molecular mechanisms and relevant FIH substrate proteins. Also, the molecular mechanism(s) involved in the physiological functions of FIH remain(s) to be determined. Furthermore, the therapeutic potential of recently developed FIH-selective pharmacologic inhibitors will need detailed assessment. Antioxid.

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“…Noticeably, Yang YW et al. ( 122 ) found that two circRNAs (circ_2909 and circ_0323) could promote the expression of HIF-1α and inducible nitric oxide synthase (NOS2) by acting as sponges for miRNAs. Furthermore, Demirci YM et al.…”

Section: Prospects Of the Clinical Application Of Circrnas In Covid-19mentioning

confidence: 99%

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

Gao¹,

Fang²,

Liang³

et al. 2022

Front. Immunol.

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Coronavirus disease 2019 (COVID-19), an infectious acute respiratory disease caused by a newly emerging RNA virus, is a still-growing pandemic that has caused more than 6 million deaths globally and has seriously threatened the lives and health of people across the world. Currently, several drugs have been used in the clinical treatment of COVID-19, such as small molecules, neutralizing antibodies, and monoclonal antibodies. In addition, several vaccines have been used to prevent the spread of the pandemic, such as adenovirus vector vaccines, inactivated vaccines, recombinant subunit vaccines, and nucleic acid vaccines. However, the efficacy of vaccines and the onset of adverse reactions vary among individuals. Accumulating evidence has demonstrated that circular RNAs (circRNAs) are crucial regulators of viral infections and antiviral immune responses and are heavily involved in COVID-19 pathologies. During novel coronavirus infection, circRNAs not only directly affect the transcription process and interfere with viral replication but also indirectly regulate biological processes, including virus-host receptor binding and the immune response. Consequently, understanding the expression and function of circRNAs during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will provide novel insights into the development of circRNA-based methods. In this review, we summarize recent progress on the roles and underlying mechanisms of circRNAs that regulate the inflammatory response, viral replication, immune evasion, and cytokines induced by SARS-CoV-2 infection, and thus highlighting the diagnostic and therapeutic challenges in the treatment of COVID-19 and future research directions.

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ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway

Cited by 9 publications

References 44 publications

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits

The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

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