Subverting Host Cell P21-Activated Kinase: A Case of Convergent Evolution across Pathogens

Abstract

Intracellular pathogens have evolved a wide range of strategies to not only escape from the immune systems of their hosts, but also to directly exploit a variety of host factors to facilitate the infection process. One such strategy is to subvert host cell signalling pathways to the advantage of the pathogen. Recent research has highlighted that the human serine/threonine kinase PAK, or p21-activated kinase, is a central component of host-pathogen interactions in many infection systems involving viruses, bacteria, and eukaryotic pathogens. PAK paralogues are found in most mammalian tissues, where they play vital roles in a wide range of functions. The role of PAKs in cell proliferation and survival, and their involvement in a number of cancers, is of great interest in the context of drug discovery. In this review we discuss the latest insights into the surprisingly central role human PAK1 plays for the infection by such different infectious disease agents as viruses, bacteria, and parasitic protists. It is our intention to open serious discussion on the applicability of PAK inhibitors for the treatment, not only of neoplastic diseases, which is currently the primary objective of drug discovery research targeting these enzymes, but also of a wide range of infectious diseases.

Manipulating Eryptosis of Human Red Blood Cells: A Novel Antimalarial Strategy?

“…Further, P. falciparum activates and relies on human kinases such as mitogen-activated protein kinase kinase (MEK) and p21 activated kinase (PAK), for its development inside RBCs (Sicard et al, 2011 ). Interestingly, PAK kinases have the ability to inhibit eryptosis in energy depletion conditions, as discussed above (Zelenak et al, 2011 ) and are often subverted by pathogens for different cellular functions, including manipulation of apoptosis (John von Freyend et al, 2017 ). Overall, even though there is currently no direct evidence that PAK activation in iRBCs is linked to eryptosis manipulation, it is an exciting hypothesis that opens great perspectives for anti-malaria intervention strategies.…”

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

“…Besides the critical roles in cancer, PAKs are important for infectious diseases through regulating several host-driven responses to pathogen infection, through anti-pathogen signal transduction and immune regulation ( John Von Freyend et al, 2017 ). PAK1 and PAK2 affect infection progression (virus, bacteria, and parasitic protists) at various stages, promoting pathogens entry into, replication within, survival, and secretion from host cells.…”

Evidence of a dysregulated Vitamin D pathway in SARS-CoV-2 infected patient’s lung cells

“…The PAK family of cellular kinases has been found to be activated by pathogens, including RNA viruses such as influenza and HIV 51,52 . Over the years, PAKs have been implicated in various stages of virus entry and replication and in supporting the cell survival phenotype during certain viral infections 20 . To understand the significance of the PAK pathway in SARS-CoV-2 pathobiology, we first examined the status of PAKs in SPPD.…”

“…For productive infection, many viruses use the host machinery to antagonize the host defense mechanism while using survival pathways to abort apoptosis for ensuring a successful completion of their replication and generation of progeny virions. In this context, previous work suggest that during the host-RNA-virus interaction, pathogen replication and its propagation are profoundly influenced by human p21-activated kinases (PAKs) 20 , which are the established modifiers of cytoskeleton remodeling, inflammation, thrombosis, cell survival, and gene expression or repression, in addition to its oncogenic role in cancer development progression [21][22][23][24][25] . However, to the best of our knowledge, no published data exist about the effect of SARS-CoV-2 on PAK mRNA expression levels in the context of the vitamin D pathway.…”