The state of the septin cytoskeleton from assembly to function

Woods, Benjamin; Gladfelter, Amy S.

doi:10.1016/j.ceb.2020.10.007

Cited by 102 publications

(80 citation statements)

References 71 publications

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“…Alongside microtubules, actin and intermediate filaments, septins comprise a distinct filamentous network with important functions in cellular morphogenesis and physiology [1][2][3][4] . Septins were originally discovered in the budding yeast Saccharomyces cerevisiae as a network of filaments that associates with the motherbud neck domain of the plasma membrane and controls the localization of many proteins with roles in cell division and growth 2,5,6 .…”

Section: Introductionmentioning

confidence: 99%

Cellular functions of actin- and microtubule-associated septins

2021

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Section: Introductionmentioning

confidence: 99%

Cellular functions of actin- and microtubule-associated septins

2021

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“…Septins are highly conserved cytoskeletal proteins whose assembly into heterooligomers is important for various cellular processes (Mostowy and Cossart 2012;Woods and Gladfelter 2021). Septins were originally discovered in Saccharomyces cerevisiae as temperature-sensitive (TS) mutants that failed to complete cytokinesis at high temperature (Hartwell 1971).…”

Section: Introductionmentioning

confidence: 99%

Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

Denney

Weems

McMurray

2021

Preprint

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Life requires the oligomerization of individual proteins into higher-order assemblies. In order to form functional oligomers, monomers must adopt appropriate three-dimensional structures. Molecular chaperones transiently bind nascent or misfolded proteins to promote proper folding. Single missense mutations frequently cause disease by perturbing folding despite chaperone engagement. A misfolded mutant capable of oligomerizing with wild-type proteins can dominantly poison oligomer function. We previously found evidence that human-disease-linked mutations in Saccharomyces cerevisiae septin proteins slow folding and attract chaperones, resulting in a kinetic delay in oligomerization that prevents the mutant from interfering with wild-type function. Here we build upon our septin studies to develop a new approach to identifying chaperone interactions in living cells, and use it to expand our understanding of chaperone involvement, kinetic folding delays, and oligomerization in the recessive behavior of tumor-derived mutants of the tumor suppressor p53. We find evidence of increased binding of several cytosolic chaperones to a recessive, misfolding-prone mutant, p53(V272M). Similar to our septin results, chaperone overexpression inhibits the function of p53(V272M) with minimal effect on the wild type. Unlike mutant septins, p53(V272M) is not kinetically delayed under conditions in which it is functional. Instead, it interacts with wild-type p53 but this interaction is temperature sensitive. At high temperatures or upon chaperone overexpression, p53(V272M) is excluded from the nucleus and cannot function or perturb wild-type function. Chaperone inhibition liberates the mutant to enter the nucleus where it has a slight dominant-negative effect. These findings provide new insights into the effects of missense mutations.

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“…Septins associate in a dynamic way with different major constituents of the cell, i.e. membranes, actin fibers and microtubules 6 . Septin octamers and hexamers co-associate to form septin filaments 7,8,[10][11][12][13] , whose properties may depend in part on the relative abundance of incorporated octamers and hexamers.…”

Section: Discussionmentioning

confidence: 99%

“…Septins are GTP-binding protein that form heteropolymeric complexes associating with membranes, actin filaments and a subset of microtubules 6 . Like yeast and Drosophila septins, human septin hexameric and octameric protomers can polymerize into filaments [7][8][9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Septin-microtubule association requires a MAP-like motif unique to Sept9 isoform 1 embedded into septin octamers

Kuzmić

Linares

Fialova

et al. 2021

Preprint

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Septins, a family of GTP-binding proteins assembling into higher order structures, interface with the membrane, actin filaments and microtubules, which positions them as important regulators of cytoarchitecture. Septin 9 (Sept9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short MAP-like motif unique to Sept9 isoform 1 (Sept9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring Sept9_i1. Although outside of the MAP-like motif, HNA mutations abrogates this association, identifying a putative regulatory domain. Removal of this domain from Sept9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin associated pathologies.

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The state of the septin cytoskeleton from assembly to function

Cited by 102 publications

References 71 publications

Cellular functions of actin- and microtubule-associated septins

Cellular functions of actin- and microtubule-associated septins

Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

Septin-microtubule association requires a MAP-like motif unique to Sept9 isoform 1 embedded into septin octamers

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