An Internalization Wave of Caveolae can be Stimulated by Virus

Studies on the entry of simian 40 (SV40) virus by Pelkmans and coworkers [52-54] have documented that caveolae can actually play a role in nonconstitutive endocytosis. Thus, after binding of SV40 virus to the cell surface via the MHC class I molecule, the virus particles move laterally in the plasma membrane to end up in caveolae. Although these caveolae are initially immobile, the virus initiates a complex signaling cascade leading to a profound disorganization of the cortical actin cytoskeleton and a transient recruitment of the GTP-binding protein dynamin known to be involved in membrane fission (see Section 4.8). Importantly, without SV40-stimulation, less than 10% of the caveolae were associated with dynamin. These changes, in turn, resulted in a wave of incoming caveolar vesicles containing virus where reorganized actin filaments formed "tails" necessary for internali-zation of the SV40-containing caveolae [53]. Subsequently, the virus was delivered to caveosomes (see Section 4.7) and transported further downstream to the endoplasmic reticulum (ER). However, a delay of several hours then occurs before caveolin returns from the caveosomes to the plasma membrane in vesicles now devoid of virus particles [52].

It is interesting to note that antibody-induced crosslinking of MHC class I molecules (the SV40 receptor) results in an accumulation of MHC class I clusters in "small uncoated surface invaginations" identical to caveolae, as reported 25 years ago by Huet and coworkers. No clusters were found in clathrin-coated pits. From the caveolae-like invaginations the clusters were apparently internalized and delivered to lysosomes [55]. It is therefore tempting to speculate that it is the same underlying mechanism that is responsible for caveolae-mediated uptake of SV40 virus particles after their binding to MHC class I and of MHC class I clusters generated by antibody crosslinking.

Echovirus 1 is also taken up by caveolae, and binds to the collagen receptor a2Pi integrin [56]. Interestingly, recent studies revealed that a2bi is localized to non-caveolar rafts, but that antibody crosslinking clustered a2p1 in caveolae, which subsequently became internalized and delivered the integrin to caveosome-like structures. This internalization is dependent on protein kinase Ca activity [57]. In the same study it was revealed that aV integrin clusters are not taken up by caveolae, but via clathrin-coated pits and vesicles. The common human polyomavirus BK also seems to become internalized by caveolae [58]. It should be stressed, however, that several types of virus are internalized in a clathrin-dependent manner, the classical example being Semliki Forest virus [59], although other recent examples include rubella virus [60] and bovine viral diarrhea virus (a pest virus) [61].

In an ultrastructural study, Parton and co-workers [62] found that the treatment of cells with the phosphatase inhibitor okadaic acid leads to aggregation and subsequent internalization of caveolae, and that the process is dependent on an intact actin cytoskeleton since treatment with cytochalasin D could prevent it. These results suggest that okadaic acid somehow induces a reorganization of actin. The okadaic acid-induced internalization of caveolae was later confirmed by FLIP studies on fluorescent caveolin-expressing cells. Thus, after okadaic acid treatment, plasma membrane caveolin/caveolae gradually disappear from the plasma membrane and aggregate in the perinuclear region, and the mobility of caveolin clearly increased so that the repeated bleaching cycles almost completely extracted the entire cellular fluorescence signal [31].

Finally, a rather special example of a caveolin/caveolae-stimulated internaliza-tion should be mentioned. Thus, FimH-expressing Escherichia coli are, via binding of the bacteria to CD48 on macrophages and mast cells, apparently able to recruit and cluster caveolae, eventually leading to the formation of intracellular, bacteria-containing compartments [63,64].

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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