13. SARS-CoV-2 Spike Protein suppresses DUSPs to Further Induce Neurodegeneration
In addition to Wip1, dual-specificity phosphatases [DUSPs] are a large heterogeneous group of protein phosphatases that can dephosphorylate serine, threonine and tyrosine residues on a large number of proteins. Many of the proteins that they dephosphorylate are part of the MAPK cascade, and therefore they can be effective to turn off MAPK activation and resolve an inflammatory response [111].
Because DUSP genes, especially DUSP1 protein, are negative regulators of p38 MAPK signaling, their reduction under TLR4 signaling will sustain the activation of both p38 MAPK and c-Jun NH2 terminal kinase (JNK) pathways [85,112,113].
As we have seen, several multidisciplinary studies provide evidence of activation of TLR2/4 signaling by the SARS-CoV-2 spike protein [10,11,30,31,86]. Especially in nerve cells, the S1 subunit of the spike protein activates p38 MAPK and NF-κB through upregulation of expression and activation of TLR4 pattern recognition receptor [10]. Furthermore, exposure of human macrophages to the spike protein activates the phosphorylation of IRAK4 and the subsequent p38 MAPK and JNK pathways, and resulting suppression of autophagy [82].
Notably, SARS-CoV-2 infection and subsequent cleavage of the spike protein by the transmembrane protease/serine subfamily 2 (TMPRSS2) / p38 MAPK pathway activates MAPK phosphorylation and NF-κB signaling by reducing the transcriptional activation of DUSP1 and DUSP5 [114]. This is a unique property of SARS-CoV-2 compared to all other coronaviruses. Moreover, p53 has been shown to enhance the post-transcriptional maturation of miR-16 [79], and, as we have seen, miR-16 has been shown to downregulate expression of Wip1 [76].
Thus, the Wip1 and DUSP inhibitory activity upon p53, p38 MAPK, and ATM will both be attenuated in the presence of the spike protein. As a consequence, there will be sustained production of inflammatory cytokines, and an increased tendency towards cellular senescence and apoptosis [91]. β-Amyloid (Aβ) production occurs in various cell types and in many organs [103,115]. However, in cells orchestrating simultaneous Aβ / AICD production and PrPC expression, i.e., neurons, the spike-protein-induced impairment of the phosphatase pathways will have deleterious effects, with significant implications for cellular neurotoxicity [116,117].
The excess phosphorylated p53 from the suppression of Wip1 and DUSP dephosphorylation activities acts as a transcriptional activator of the prion protein promoter to produce an excess of PrPC, creating an environment for prion disease development. Since presenilin-dependent γ-secretase works in concert with p53 by enhancing its expression through producing AICD and Aβ, it thus worsens the preconditioning of spike-protein-induced neurotoxicity in this system. Furthermore, the increased expression of transcription factor AP-1 by the phosphorylated c-Jun triggers the promoters of APP andPRNP for further transcriptional activation [97,115].
Common transcription factor activation located in both APP andPRNP promoters, such as by the selective promoter factor 1 (SP1), happens during the inflammatory response in AD brain. Among many other important roles, AP-1 regulates the transcription of BACE-1, and tau protein subsequently promotes the development of neurotoxicity [118-120]. The condition can be described as ‘Wip1 and DUSP deficiency-p53 mediated induction of prion and prion-like disease induced by the SARS CoV-2 spike glycoprotein’ and is illustrated in Figure 1.