Nature Reviews Molecular Cell Biology

Chesarone, Melissa A.; DuPage, Amy Grace; Goode, Bruce L.

doi: 10.1038/nrm2816pmid: 19997130

Formins are a large family of conserved proteins, defined by the presence of formin homology 1 (FH1) and FH2 domains, that directly stimulate actin assembly. Outside of these domains, formins show wide variation in their sequences, which specify key differences in their regulation. Formins promote de novo actin assembly, and their FH2 domains remain processively attached to the elongating end of the filament. Through interactions of their FH1 domains with profilin–actin, formins accelerate, to different degrees, actin addition at filament ends. Recent work has shown that some formins also regulate microtubule dynamics in vivo and in vitro, but the specific mechanistic role of formins in this capacity is yet to be determined. Emerging evidence suggests that formin activities are regulated in vivo at multiple points, including the initial recruitment and activation of formins at membranes, actin nucleation and elongation, and the displacement, inactivation, recycling and turnover of formins. A growing list of formin binding partners has been implicated in the regulation of formin activities, suggesting that multiple signalling pathways converge on formins to trigger cytoskeletal remodelling. Further work is required to elucidate their mechanisms and understand how formins are harnessed to different cellular tasks.

David, Rachel

doi: 10.1038/nrm2819pmid: 20050309

WASH multiprotein complex has an integral role in endosomal sorting.

Casey, Joseph R.; Grinstein, Sergio; Orlowski, John

doi: 10.1038/nrm2820pmid: 19997129

In eukaryotic cells, the steady-state pH of intracellular compartments varies greatly, is tightly controlled and is an important determinant of their function. In general, the cytoplasm tends to acidify as a result of catabolism and a negative membrane potential that drives the accumulation of H+ through cation channels and the loss of basic HCO3 − through anion channels. Countering this acidification are intrinsic buffers (ionizable groups on amino acids, phosphates and other molecules) and HCO3 −, which have a finite capacity, as well as distinct plasma membrane pH-regulatory transporters (for example, Na+–H+ exchangers and bicarbonate transporters) that finely control pH to keep it close to neutral — a level that is optimal for many protein interactions and cellular processes. Some organelles, including the nucleus, endoplasmic reticulum and peroxisomes, seem to lack intrinsic pH-regulatory systems and instead seem highly permeable to H+ (or acid equivalents). Hence, these compartments readily equilibrate their luminal pH to levels found in the cytoplasm. Organelles of the secretory and endocytic pathways are distinguished by their luminal acidity (pH 6.7–4.7), which is attained through the concerted actions of vacuolar H+–ATPases, 2 Cl−/1 H+ and Na+–H+ or K+–H+ exchangers. Progressive acidification of organelles along the secretory pathway is important for proper post-translational processing, sorting and transport of newly synthesized proteins. Likewise, graded acidification of vesicles along the endocytic pathway is essential for the recycling and/or degradation of internalized membrane proteins, fluid-phase solutes and entry of various microbial organisms. By contrast, the mitochondrial matrix is quite alkaline (pH 8.0) owing to H+ extrusion across the inner membrane by components of the electron transport chain. Together with the electrical potential (inside negative) generated by the electrogenic proton extrusion process, the transmembrane pH gradient constitutes a proton-motive force that is harnessed by the inner membrane H+-ATP synthase (F1F0-ATPase) to generate ATP from ADP and inorganic phosphate. Many cellular processes are exquisitely sensitive to changes in the surrounding pH. Fluctuations in the H+ concentration in some cases act as a general permissive factor, whereas in other cases they act directly as a regulatory signal.