Exploring the Lung-Related Protein CRTAC1: Implications in COVID-19 Pathogenesis and Beyond

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The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has had profound effects on global health. As researchers continue to unravel the complexities of this viral infection, many aspects of its pathophysiology and its impact on the human body remain a subject of intense investigation.

In a mass spectrometric study conducted early in the COVID-19 pandemic, researchers made a significant discovery regarding the plasma protein Cartilage Acidic Protein 1 (CRTAC1) (Overmyer et al., 2021).

This study found that CRTAC1 levels decreased significantly in patients with COVID-19, particularly those with deteriorating respiratory status.

CRTAC1, a relatively understudied protein with an obscure function, has raised significant interest due to its intriguing links to COVID-19. In this article, we delve into the findings of this study and explore the potential implications of low CRTAC1 levels in COVID-19 patients.

We also discuss the possible mechanisms behind these changes and their significance, including their association with the alternate complement pathway and long COVID.

The Initial Discovery

The initial study by Overmyer et al. (2021) employed mass spectrometry to measure CRTAC1 levels in a cohort of patients with COVID-19. The results showed a marked decrease in CRTAC1 levels, particularly in individuals with severe respiratory symptoms. This decline was also observed in subsequent studies by Byeon et al. (2022) and Shen et al. (2020), further emphasizing the association between low CRTAC1 levels and severe COVID-19. These studies used tandem mass tagging to compare subjects with non-severe and severe disease, corroborating the initial findings.

CRTAC1’s Link to SARS-CoV-2

The connection between CRTAC1 and COVID-19 becomes even more intriguing when considering its genetic proximity to GOLGA7B, a gene required for the palmitoylation of the SARS-CoV-2 spike protein, which is crucial for viral infectivity (Wu et al., 2021). This suggests that CRTAC1 may play a role in the viral life cycle or host response to infection.

Additionally, CRTAC1 is produced by Type 2 alveolar epithelial (T2AE) cells, which are known to be susceptible to SARS-CoV-2 infection (Huang et al., 2020; Katsura et al., 2020). Moreover, the expression of CRTAC1 in T2AE cells increases following treatment with dexamethasone, a medication used in COVID-19 management (Ballard et al., 2010).

CRTAC1 in Lung Health

Further evidence of CRTAC1’s involvement in respiratory health comes from its association with idiopathic pulmonary fibrosis (IPF), a condition characterized by lung scarring. Mayr et al. (2021) discovered decreased levels of CRTAC1 in both plasma and bronchoalveolar lavage (BAL) of IPF patients. This finding was attributed to the loss of CRTAC1 expression by de-differentiated T2AE cells, highlighting the importance of these cells in CRTAC1 production.

Interactions with Complement Pathway

A global protein interaction screen identified CFP (properdin of the alternate complement pathway) as one of the proteins that interact with CRTAC1 (Huttlin et al., 2021). Interestingly, circulating CFP is decreased in severe COVID-19, likely due to the intense activation of the alternate complement pathway (Boussier et al., 2022; Siggins et al., 2023). This suggests a potential link between CRTAC1 and the complement system in the context of COVID-19.

Novel Findings

The current study extends our understanding of CRTAC1 in the context of COVID-19 by reporting molar concentrations of CRTAC1 using an enzyme-linked immunoassay (ELISA) in various patient groups. These groups include healthy individuals, patients hospitalized with severe COVID-19, those who have recovered from COVID-19, and individuals with chronic pulmonary disease (COPD).

The study found that CRTAC1 concentrations in patients hospitalized with severe COVID-19 were significantly lower than those in healthy individuals, reaching levels as low as 2% of the mean normal level. Importantly, the decrease in CRTAC1 levels correlated with the severity of COVID-19, suggesting that CRTAC1 may serve as a potential biomarker for disease severity. Notably, CRTAC1 also exhibited significant correlations with 173 other plasma proteins, with the most significant being CFP.

The authors went on to demonstrate that soluble recombinant CRTAC1 interacts with insolubilized recombinant CFP, providing evidence for a potential mechanistic link between CRTAC1 and the complement pathway. This suggests that the decrease in CRTAC1 associated with severe COVID-19 could result from increased turnover due to complement pathway activation. Additionally, the loss of production of CRTAC1 by de-differentiated T2AE cells, as observed in IPF, may further contribute to low plasma CRTAC1 levels in COVID-19.

One particularly intriguing aspect of the study is the finding that some patients continued to have low plasma CRTAC1 levels even a year after hospitalization with severe COVID-19, as well as in a subset of long COVID patients who did not require hospitalization. This raises questions about the long-term effects of COVID-19 on CRTAC1 levels and the potential significance of these persistently low concentrations.

Discussion

The mass spectrometric study conducted by Overmyer et al. (2021) shed light on the previously understudied protein CRTAC1 and its association with COVID-19. However, it also raised several questions and avenues for further research. Here, we discuss the implications of these findings and the potential mechanisms behind low CRTAC1 levels in COVID-19.

Structural Insights into CRTAC1

CRTAC1 is a complex protein with distinct neural and nonneural proteoforms. The neural proteoform has been identified as LOTUS, playing a role in axonal growth and synaptic density in the brain (Sato et al., 2011). It interacts with reticulon-4 receptor (RTN4R), a protein known to inhibit axon growth.

The nonneural proteoform of CRTAC1 is primarily synthesized in the lung and cartilage (Steck et al., 2007). While the neural CRTAC1 has been studied extensively, it remains unclear whether the nonneural form plays a role in COVID-19-related CNS symptoms, such as anosmia. Further research is needed to establish whether nonneural CRTAC1 crosses the blood-brain barrier and contributes to neuronal connections in COVID-19 patients.

Potential Mechanisms of Low CRTAC1

The study suggests that low circulating CRTAC1 in severe COVID-19 may result from multiple mechanisms. First, the contribution of T2AE cells to circulating CRTAC1 is likely impacted by the loss of these cells during severe COVID-19 and the remodeling of the lung epithelium.

Additionally, de-differentiation of T2AE cells may result in the secretion of CRTAC1 into the airway space rather than the circulation. This disruption in polar secretion may be due to alterations in T2AE cell positioning on basal lamina.

Moreover, CRTAC1 may interact with and deposit alongside CFP at sites of alternative complement pathway activation. This interaction could further deplete circulating CRTAC1, amplifying the loss of production from T2AE cells. Patients recovering from COVID-19, in whom CRTAC1 fails to return to normal levels, may continue to experience disruptions in T2AE cells or ongoing complement activation, or a combination of both.

Limitations and Future Directions

While this study provides valuable insights, it has certain limitations. The enrolled COVID-19 patients were part of the initial phase of the pandemic and may not fully represent the patient population in more recent phases. Future research should consider the impact of new SARS-CoV-2 variants, evolving treatment strategies, and preexisting immunity on CRTAC1 levels.

Furthermore, the study’s non-COVID-19 patient cohort was smaller and more heterogeneous. Additional investigations are needed to determine the range of CRTAC1 concentrations in other respiratory conditions, such as influenza and viral pneumonias. Additionally, the subset of long COVID patients with persistently low CRTAC1 warrants further study to understand the underlying factors contributing to this phenomenon.

Conclusion

In conclusion, the study of CRTAC1 in the context of COVID-19 presents an intriguing avenue of research. Low CRTAC1 levels in severe COVID-19 patients and their potential implications on disease severity, long COVID, and the complement pathway raise numerous questions and opportunities for further exploration. Understanding the role of CRTAC1 in COVID-19 may not only lead to improved diagnostics and prognostics but also provide insights into the intricate host-virus interactions underlying this global health crisis. As the COVID-19 pandemic continues to evolve, ongoing research into the biology of CRTAC1 promises to shed light on new aspects of the disease and its aftermath.

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