Quick flip = one-way proton trip

Take a big gulp of pox A poxvirus tricks cells into drinking it up, say Jason Mercer and Ari Helenius (Institute of Biochemistry, Zurich). Vaccinia, studied here, is a prototypical poxvirus, whose members also include the human smallpox virus. In studying how vaccinia enters cells, the authors observed that mature virus particles bound to fi lopodia and surfed toward the cell. After arriving at the cell body, the virus particles induced the entire cell surface to erupt into blebs, which, when retracting, engulfed the virus. To the authors’ amazement, a single virus particle was suffi cient to induce this dramatic behavior. Entry could be inhibited by the myosin II inhibitor, blebbistatin, as well as by inhibitors of actin dynamics and endosomal fusion. These and other clues, such as the requirement of p21-activated kinase and Na+/H+ exchangers, pointed to a central role for macropinocytosis in viral entry. As confi rmation, the authors showed that fluid-phase, but not clathrinmediated, markers were internalized along with the virus. “This is the fi rst connection of blebbing and macropinocytosis in eukaryotes,” says Mercer. One function of macropinocytosis is engulfment of apoptotic debris, which is triggered by contact between the engulfi ng cell and membranes with exposed phosphatidylserines (PS), which are normally hidden on the inner membrane surface of cells. The vaccinia membrane is known to be rich in PS, and when the authors blocked PS, infectivity dropped; the virus still bound to cells, but no blebbing or entry occurred. “It’s a beautiful way to invade a lot of different cell types,” Mercer says, “because uptake of phosphatidylserine is such a general mechanism. The virus is taking advantage of a system the cell can’t get rid of.” Mercer, J., and A. Helenius. 2008. Science. 320:531–535. Signaling specifically from the endosome F or Akt signaling, location matters, according to Annette Schenck, Marino Zerial (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany), and colleagues. Akt (protein kinase B) infl uences a wide variety of pathways in the cell, but how it divides its activity between them was unclear. Akt is known to signal from the plasma membrane, but an upstream regulator of Akt called APPL1, which is known to interact directly with Akt, has been reported to reside on endosomes. Here, the authors showed that loss of APPL1 affected the activity of some downstream targets of Akt, but not others. For example, the activity of Gsk-3β, an Akt target involved in cell survival, was diminished by APPL1 loss, while the activity of Tsc2, an Akt target that promotes growth, was unaffected. These differential effects were tied to differences in location: Gsk-3β, but not Tsc2, linked up with Akt and APPL1 on the endosome. And the endosomal location was clearly important, since neither nuclear-targeted nor cytosolic APPL1 could rescue cells with depleted endosomal APPL1. “This is the fi rst time Akt signaling has been shown from the endosome,” Zerial says. “We think these results should make the signaling community take seriously the contribution of endocytic traffi cking to the quality and quantity of signaling.” Schenck, A., et al. 2008. Cell. 133:486–497.