An emerging role for p21-activated kinases (Paks) in viral infections

Abstract

p21-activated protein kinases (Paks) are cytosolic serine/threonine protein kinases that act as effectors for small (p21) GTPases of the Cdc42 and Rac families. It has long been established that Paks play a major role in a host of vital cellular functions such as proliferation, survival and motility, and abnormal Pak function is associated with a number of human diseases. Here, we discuss emerging evidence that these enzymes also play a major role in the entry, replication and spread of many important pathogenic human viruses, including HIV. Careful assessment of the potential role of Paks in antiviral immunity will be pivotal to evaluate thoroughly the potential of agents that inhibit Pak as a new class of anti-viral therapeutics.

Figure 1.

Structural comparison of group I and group II Paks. Group I Pak members share a high degree of homology. The N-terminal part constitutes the regulatory region and contains the p21-binding domain that overlaps with the autoinhibitory domain. The C terminal part has a kinase domain that is more than 90% conserved among Pak I members. Group II Paks have the same domains, but they lack the autoinhibitory domain. The kinase domain of group II Paks is less conserved than that of group I Pak members.

Figure 2.

Pak1 and Pak2 amino acid sequence alignment. Conserved residues are marked by stars. The PxxP motif is responsible for binding of the adaptor protein Nck, whereas the CRIB motif is responsible for binding Cdc42. Delimitation between the regulatory and the catalytic region is shown by brackets. The arrow indicates the aspartic acid at position 212 that identifies the caspase cleavage site in Pak2, but not in Pak1. Binding of Nef to Pak is not dependent on the presence of the PxxP motif, Pix binding site, CRIB motif or the caspase cleavage site within Pak2. The Pak sequence important for Nef binding is underlined in red.

Figure 3.

Virus-mediated activation of Pak. The figure shows the different virus families, and if known the virus protein and downstream signaling cascades, that lead to Pak activation at some point during the virus replication cycle. The best-studied viral activation of Paks takes place in HIV infection where Paks are activated by the virus Nef protein via a Nef–Vav–Rac1–Cdc42 complex. Pak, p21-activated kinase; PI3K, phosphoinositide 3-kinase; Hbx, Hepatitis B virus X protein; GPCR, G-protein-coupled receptor; VV, vaccinia virus; EV1, echovirus 1; HIV, human immunodeficiency virus; PRV, pseudorabies virus; KSHV, Kaposi’s sarcoma-associated herpesvirus.

Figure 4.

Consequences of virus-mediated activation of Pak. Activation of Pak by a wide variety of viruses may lead to (i) cytoskeletal rearrangements such as cortical actin disassembly, macropinocytotic virus uptake, actin stress fiber disassembly and projection formation, (ii) anti-apoptotic signaling, (iii) oncogenesis, (iv) immune evasion and (v) antiviral signaling. Pak, p21-activated kinase; PRV, pseudorabies virus; HSV, herpes simplex virus; HIV, human immunodeficiency virus; EV1, echovirus 1; HCV, hepatitis C virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; HBV, hepatitis B virus; VV, vaccinia virus; Ad3, adenovirus 3; DC, dendritic cell.