Michael Way

Michael Way : Vaccinia F11, a PDZ scaffolding protein that inhibits RhoA by binding Myosin-9


Vaccinia needs to traverse the cortical actin cytoskeleton.

Prior to fusing with the plasma membrane and inducing actin polymerisation, vaccinia needs to traverse the cortical actin cytoskeleton.

The cortical actin, which is regulated by RhoA signalling, provides the cell with mechanical resilience and represents a significant physical barrier to the spread of infection.

Vaccinia scaffolding proteins.

We have previously demonstrated that vaccinia inhibits RhoA signalling using F11, a viral protein that interacts directly with RhoA using a motif that is also found in the RhoA effector ROCK (Valderrama et al., 2006; Science. 311: 377-81).

During infection, F11-mediated inhibition of RhoA signalling stimulates cell migration, increases microtubule dynamics and also enhances viral release by modulating the cortical actin beneath the plasma membrane. F11 promotes viral spread by binding RhoA, however, the mechanistic basis of this inhibition remained to be established.

We have now found that F11 contains a central PDZ-like domain that is required to down regulate RhoA signalling and enhance viral spread (Handa et al., 2013; Cell Host Microbe. 14: 51-62). The F11 PDZ-like domain interacts with the PDZ binding motif of the RhoGTPase activating protein (GAP) Myosin-9A.

In the absence of Myosin-9A, RhoA signalling is not inhibited resulting in fewer CEV inducing actin polymerisation and reduced virus release concomitant with less viral spread.

The loss of the GAP activity of Myosin-9A or its ability to bind F11 also reduces the number of CEV inducing actin polymerisation. Furthermore, the ability of Myosin-9A to promote viral spread also depends on the capacity of F11 to bind RhoA.

Our observations demonstrate that F11, which is the first example of a viral protein with a functional PDZ domain, acts as a scaffolding protein to inhibit RhoA signalling by binding Myosin-9A (Handa et al., 2013).