Chronic obstructive pulmonary disease (COPD) was the third leading cause of global death in 2019, causing a huge economic burden to society. Therefore, it is urgent to identify specific phenotypes of COPD patients through early detection, and to promptly treat exacerbations. The field of phosphoproteomics has been a massive advancement, compelled by the developments in mass spectrometry, enrichment strategies, algorithms, and tools. Modern mass spectrometry-based phosphoproteomics allows understanding of disease pathobiology, biomarker discovery, and predicting new therapeutic modalities.
In this article, we present an overview of phosphoproteomic research and strategies for enrichment and fractionation of phosphopeptides, identification of phosphorylation sites, chromatographic separation and mass spectrometry detection strategies, and the potential application of phosphorylated proteomic analysis in the diagnosis, treatment, and prognosis of COPD disease.
The role of phosphoproteomics in COPD is critical for understanding disease pathobiology, identifying potential biomarkers, and predicting new therapeutic approaches. However, the complexity of COPD requires the more comprehensive understanding that can be achieved through integrated multi-omics studies. Phosphoproteomics, as a part of these multi-omics approaches, can provide valuable insights into the underlying mechanisms of COPD.
Phosphorylation is a posttranslational modification of proteins, a reversible process by which kinases translocate phosphate groups from ATP to protein residues, and phosphatases dephosphorylate proteins. The addition of phosphate groups to proteins can affect many properties of the proteins, including protein folding, activity, interaction with other proteins, and localization or degradation [1]. Therefore, phosphorylation plays a crucial role in regulating almost all biological phenomena and virtually all physical phenomena, such as cell proliferation, development, differentiation, signal transduction, apoptosis, neural activity, muscle contraction, metabolism, and tumorigenesis [2, 3].Chronic obstructive pulmonary disease (COPD) is characterized by not fully reversible airflow limitation, varying with cough, phlegm, wheezing, breathlessness, and comorbidities in clinical manifestations. The typical COPD phenotype is mainly chronic airway inflammation, and emphysema type, while special patients will have a more refined inflammatory phenotype. Fibrotic lesions can be found in the small airways and can contribute to small airway obstruction in COPD [4]. This can cause difficulties in breathing and can lead to more severe symptoms of COPD. Different phenotypes of patients have different degrees of expiratory airflow limitation [5]. Asthma is characterized by airway narrowing due to bronchoconstriction and airway inflammation. Asthma may be a risk factor for COPD. In severe asthma, structural changes such as airway remodeling can lead to airway obstruction and a narrower inner diameter of the airway. Approximately 15-20% of COPD patients have features of both of these diseases [6], which is termed asthma-COPD overlap (ACO). Whether COPD, asthma, or ACO, they are all characterizes as heterogeneous diseases, which means more disease burden and challenges to current diagnostic and therapeutic strategies.In recent years, there is increasing evidence of the important role of phosphorylation events in the pathogenesis of COPD. For example, we all know that the formation of neutrophil extracellular traps is associated with the severity of COPD [7], and the activation of the Raf-MEK-ERK pathway, which is essential for the formation of neutrophil extracellular traps, involves a series of phosphorylation events [8]. In 2021, Gao et al. [9] found that JNK pathway-associated phosphatase (JKAP) may have the potential as a biomarker for the risk of acute exacerbation in COPD patients in serum samples from COPD patients. In addition, it was found that the expression of IL36γ in bronchoalveolar lavage fluid from COPD patients was increased compared to the control, while the expression of IL-36Ra decreased [10]. The molecular mechanism here can be explained by IL36 promoting lung inflammation through the activation of certain signaling pathways, such as the MAPKs-NF-κB pathways, which also involve a series of phosphorylation events [11].Taken together, phosphoproteomics technology is promising for the study of COPD. The Phosphoproteomics approach can be used to tailor medical treatment to an individual’s specific characteristics to improve its effectiveness and efficiency. However, phosphoproteins are characterized by low abundance, high complexity, and high dynamics, limiting the development of phosphoproteomics research in COPD. This paper focuses on phosphopeptide enrichment and fractionation methods, identification of phosphorylation sites, chromatographic separation and mass spectrometry detection strategies, and potential application of phosphoproteomics in COPD by introducing phosphorylation events.