Disease relevance of Gsn

• Unphosphorylated gelsolin is localized in regions of cell-substratum contact or attachment in Rous sarcoma virus-transformed rat cells [1].
• Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis [2].

High impact information on Gsn

• Caspase-3 cleaves several essential downstream substrates involved in the expression of the apoptotic phenotype in vitro, including gelsolin, PAK2, fodrin, nuclear lamins and the inhibitory subunit of DNA fragmentation factor [3].
• By immunogold labeling, we demonstrate that "millipede-like" structures seen previously in mammalian cell cytoskeletons after removal of actin by treatment with gelsolin are composed of the cores of vimentin IFs with sidearms containing plectin [4].
• The association of IFs with stress fibers survived actin depletion by gelsolin suggesting that myosin II minifilaments or components closely associated with them may play a role as plectin targets [4].
• In this study, we examined the role of actin filaments in regulated exocytosis by introducing highly specific actin monomer-binding proteins, the beta-thymosins or a gelsolin fragment, into streptolysin O-permeabilized pancreatic acinar cells [5].
• 5. Using a sedimentation binding assay that uses gelsolin to shorten actin filaments and render membrane binding saturable (Schwartz, M. A., and E. J. Luna. 1986. J. Cell Biol. 102:2067-2075), we found that membranes stripped of endogenous actin bound 125I-actin in a specific and saturable manner [6].

Biological context of Gsn

• Using the epididymis as a model system in which luminal acidification is crucial for sperm maturation and storage, we now report that modulation of the actin cytoskeleton by the calcium-activated actin-capping and -severing protein gelsolin plays a key role in regulating vacuolar H(+)-ATPase (V-ATPase) recycling [7].
• We present a model for the disassembly of the actin layer of the adhesion complex that involves the hydrolysis of PtdIns(4,5)P(2) resulting in the release of gelsolin within the plaque [8].
• Aging-associated increase of gelsolin for apoptosis resistance [9].
• Thus, we tested the sensitivity of senescent cells to apoptosis by menadione, an apoptosis-inducing agent, before and after the down-regulation of gelsolin [9].
• The ubiquitous increase of gelsolin in the aged organs and cells led us to assume that it might be related with one of the cardinal senescent phenotypes, aging-associated apoptosis resistency [9].

Anatomical context of Gsn

• Conversely, when gelsolin-mediated actin filament elongation was inhibited using a 10-residue peptide (PBP10) derived from the phosphatidylinositol 4,5-bisphosphate-binding region (phosphoinositide-binding domain 2) of gelsolin, significant V-ATPase apical membrane mobilization was induced, even at acidic luminal pH [7].
• Modulation of the actin cytoskeleton via gelsolin regulates vacuolar H+-ATPase recycling [7].
• Gelsolin is present in other cell types that express the V-ATPase in their plasma membrane and recycling vesicles, including kidney intercalated cells and osteoclasts [7].
• Treatment of isolated spermatid/junction complexes with exogenous phosphoinositide-specific phospholipase C, or with a synthetic peptide consisting of the PtdIns(4,5)P(2) binding region of gelsolin, results in the release of gelsolin and loss of actin from the adhesion complexes [8].
• In this study, we found that the level of gelsolin is elevated in senescent human diploid fibroblasts (HDFs) and also in the tissues of old rats, i.e., in the liver, kidney, heart, spleen, stomach, and brain, etc [9].

Associations of Gsn with chemical compounds

• Thus, maintenance of the actin cytoskeleton in a depolymerized state by gelsolin facilitates calcium-dependent apical accumulation of V-ATPase in response to luminal pH alkalinization [7].
• When jasplakinolide was used to overcome the severing action of gelsolin by polymerizing actin, complete inhibition of the alkaline pH- and cAMP-induced apical membrane accumulation of V-ATPase was observed [7].
• This Ca(2+) surge would facilitate the actin severing function of gelsolin within the adhesion complex [8].
• Thus, delivery of LPA to RCMs is affinity-coupled to Edg receptors by gelsolin in a PIP2-regulated process [10].
• Gelsolin binding and cellular presentation of lysophosphatidic acid [10].

Physical interactions of Gsn

• Similar short average lengths are obtained when gelsolin severs actin complexed with low Mr TMs (0.080 +/- 0.045 micron) or with nonmuscle caldesmon (0.11 +/- 0.072 micron) while longer average length (0.22 +/- 0.18 micron) is measured in the presence of high Mr TMs [11].

Regulatory relationships of Gsn

• Furthermore, the actin binding of gelsolin is strongly inhibited by co-addition of high Mr TMs and nonmuscle caldesmon [11].

Other interactions of Gsn

• Drebrin, actin, myosin, and gelsolin were co-precipitated [12].
• While nonmuscle caldesmon alone or low Mr TMs alone show no significant protection against fragmentation by gelsolin, the low Mr TMs coupled with 83-kDa protein are able to protect actin filaments [11].
• Production of PIP and PIP2 may be important downstream signals since these polyphosphoinositides are able to regulate the interaction of gelsolin and profilin with actin [13].
• These effects were corroborated in vitro using recombinant gelsolin protein on isolated rat mitochondria stimulated with Ca(2+), atractyloside, or Bax [14].
• In addition to alpha-smooth-muscle actin, these structures contain cytoplasmic actins, gelsolin and cofilin but not other major actin-binding proteins [15].

Analytical, diagnostic and therapeutic context of Gsn

• Immunoelectron microscopy revealed that gelsolin was present not only in the cytoplasm but also in compact myelin [16].
• Following solubilization by detergents, gelsolin in the myelin fraction could be purified using anion exchange and blue Sepharose column chromatographies [16].
• Plasma gelsolin was immunoprecipitated at times when actin-gelsolin complexes were present, as determined functionally, and bound actin was demonstrated by immunoblotting with an anti-actin antiserum [17].
• In addition, testicular fractions enriched for spermatid/junction complexes were incubated with and without gelsolin, centrifuged and the supernatants compared, by western blot analysis, for Glucose Regulated Protein 94 (a marker for endoplasmic reticulum) and IC74 [18].
• Double-label confocal immunocytochemistry visualized the up-regulation of gelsolin and histone acetylation within the same neuron [19].

References