Controlling pH-Dependent Condensates for Cellular Response
Background
Inflammation is a vital part of the body’s defense mechanisms, ensuring homeostasis and protecting the integrity of tissues and organs. However, excessive inflammatory responses can lead to severe tissue damage. Despite existing treatments, the fine control over inflammatory responses, particularly calibrating their magnitude and duration, remains an unmet need in medical care. Current treatments involve complex regulatory mechanisms, including negative regulators of innate sensing receptors, anti-inflammatory mediators like Il-10 and TGFb, and feedback factors such as A20 and SOCS proteins. These methods rely on constitutive expression or induction based on inflammatory stimuli, leaving gaps in precise modulation when faced with severe inflammation. Diseases such as sepsis and inflammatory bowel disease (IBD) exemplify the detrimental effects of uncontrolled inflammation, affecting millions globally. The current market for solutions continues to seek a balance between efficient immune response and minimizing pathological impacts.
Technology Overview
Researchers discovered a novel regulatory mechanism for modulating immune cell functions and responses under acidic pH, commonly associated with inflammation and solid cancer. Specifically, they found that acidic pH regulates inflammatory response in a gene-specific manner and independent of well-known pH-sensor pathways. The epigenetic regulator BRD4 was identified as a novel intracellular pH sensor. BRD4-containing transcription condensates are sensitive to pH changes and are regulated by histidine-enriched intrinsically disordered regions (IDRs). They integrate both extracellular and intracellular pH through BRD4 to trigger a gene-specific microenvironment for inflammatory responses.
Moreover, the results indicated the histidine residue enriched pH-sensitive IDRs are expected to confer pH sensitivity to polypeptides comprising/containing these sequences. Therefore, pH-sensitivity can be conferred on a heterologous protein by fusing it to a BRD4 intrinsically disordered region (IDR) or variants of BRD4-IDR; similarly, pH-sensitivity can be conferred to a cell by transducing the cell with a polynucleotide encoding the pH-sensitive BDR4-IDR region or its variants. Additionally, a PH-sensitive cellular response can be influenced by modulating the expression of heterologous BRD4-IDR region or its variants.
Applications
- Treatment of sepsis
- Treatment of inflammatory bowel disease (IBD)
- Potential use in cancers with acidic tumor microenvironments
- Treatment of other diseases characterized by excessive immune/ inflammatory responses
Advantages
- BRD4 is universally expressed, pH-sensitive mechanisms may be broadly applicable across both immune and non-immune cell types to mediate responses to inflammatory cues under acidic conditions.
- Dynamic regulation independent of standard pH sensors
- Gene-specific modulation of inflammatory responses
- Minimization of harmful impacts of inflammatory conditions
Publications
- Stephanie Hajjar & Xu Zhou. pH sensing at the intersection of tissue homeostasis and inflammation. Trends Immunol. 2023 Oct;44(10):807-825. doi: 10.1016/j.it.2023.08.008. Epub 2023 Sep 14.
- Ruslan Medzhitov. The spectrum of inflammatory responses. Science. 2021 Nov 26;374(6571):1070-1075. doi: 10.1126/science.abi5200. Epub 2021 Nov 25.
- Matthew L Meizlish, et al. Tissue Homeostasis and Inflammation. Annu Rev Immunol. 2021 Apr 26:39:557-581. doi: 10.1146/annurev-immunol-061020-053734. Epub 2021 Mar 2.
