Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility

Tooley, Aaron J.; Gilden, Julia; Jacobelli, Jordan; Beemiller, Peter; Trimble, William S.; Kinoshita, Makoto; Krummel, Matthew F.

doi:10.1038/ncb1808

Cited by 169 publications

(235 citation statements)

References 37 publications

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“…As previously described (Kremer et al, 2005;Tooley et al, 2009;Sellin et al, 2011), efficient knockdown of SEPT7 resulted in the concomitant loss of the other two members of the complex, SEPT2 and SEPT9. Under these conditions, ciliogenesis was inhibited in ,50% of cells, and the primary cilia in the remaining ,50% of cells were significantly shorter than in the control.…”

Section: Discussionsupporting

confidence: 55%

Septins 2, 7, and 9 and MAP4 co-localize along the axoneme in the primary cilium and control ciliary length

Ghossoub¹,

Hu²,

Failler³

et al. 2013

Journal of Cell Science

110

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SummarySeptins are a large, evolutionarily conserved family of GTPases that form hetero-oligomers and interact with the actin-based cytoskeleton and microtubules. They are involved in scaffolding functions, and form diffusion barriers in budding yeast, the sperm flagellum and the base of primary cilia of kidney epithelial cells. We investigated the role of septins in the primary cilium of retinal pigmented epithelial (RPE) cells, and found that SEPT2 forms a 1:1:1 complex with SEPT7 and SEPT9 and that the three members of this complex colocalize along the length of the axoneme. Similar to observations in kidney epithelial cells, depletion of cilium-localized septins by siRNA-based approaches inhibited ciliogenesis. MAP4, which is a binding partner of SEPT2 and controls the accessibility of septins to microtubules, was also localized to the axoneme where it appeared to negatively regulate ciliary length. Taken together, our data provide new insights into the functions and regulation of septins and MAP4 in the organization of the primary cilium and microtubule-based activities in cells.

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Section: Discussionsupporting

confidence: 55%

Septins 2, 7, and 9 and MAP4 co-localize along the axoneme in the primary cilium and control ciliary length

Ghossoub¹,

Hu²,

Failler³

et al. 2013

Journal of Cell Science

110

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“…This is not unexpected in light of a recent genome-wide screen for regulators of Ca 2+ signaling and nuclear factor of activated T-cells (NFAT) activation that identified septins as important modulators of store-operated Ca 2+ release, a pathway important for T-cell development and activation (Sharma et al, 2013;Fracchia et al, 2013). Moreover, septins are crucial for the maintenance of membrane dynamics, cell shape and motility in lymphocytes (Tooley et al, 2009;Gilden et al, 2012). Although septins play an important part in immune cell functions that are independent of cell division (summarized in Fig.…”

Section: Non-canonical Functions Of Septins In Immune Cellsmentioning

confidence: 94%

“…The first report addressing the requirement of septins in hematopoietic cell division came a year later. Interestingly, Krummel and co-workers analyzed the role of septins in the amoeboid migration of the murine T-lymphocytic D10.G4 cell line and observed that septin depletion had no effect on the proliferation of these cells (Tooley et al, 2009). This was followed by similar reports of septin-independent survival and proliferation of the human myeloid K562 cell line and of human T-lymphoblast jurkat cells (Sellin et al, 2011a).…”

Section: Functions Of Septins In Mammalian Cellsmentioning

confidence: 99%

“…The microtubule cytoskeleton is a prerequisite for spindle formation and mitotic chromosome segregation, and a similar and unquestionable role had been assigned to septins in animal cell cytokinesis. However, recent studies have indicated that the requirement of septins for cytokinesis is context dependent and that there are specific scenarios in which cells can undergo cytokinesis in the absence of septins (Tooley et al, 2009;Founounou et al, 2013;Guillot and Lecuit, 2013;Menon et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Menon

Gaestel

2015

Journal of Cell Science

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Cytokinesis is the final step of cell division, and is a process that requires a precisely coordinated molecular machinery to fully separate the cytoplasm of the parent cell and to establish the intact outer cell barrier of the daughter cells. Among various cytoskeletal proteins involved, septins are known to be essential mediators of cytokinesis. In this Commentary, we present recent observations that specific cell divisions can proceed in the absence of the core mammalian septin SEPT7 and its Drosophila homolog Peanut (Pnut) and that thus challenge the view that septins have an essential role in cytokinesis. In the pnut mutant neuroepithelium, orthogonal cell divisions are successfully completed. Similarly, in the mouse, Sept7-null mutant early embryonic cells and, more importantly, planktonically growing adult hematopoietic cells undergo productive proliferation. Hence, as discussed here, mechanisms must exist that compensate for the lack of SEPT7 and the other core septins in a celltype-specific manner. Despite there being crucial non-canonical immune-relevant functions of septins, septin depletion is well tolerated by the hematopoietic system. Thus differential targeting of cytokinesis could form the basis for more specific anti-proliferative therapies to combat malignancies arising from cell types that require septins for cytokinesis, such as carcinomas and sarcomas, without impairing hematopoiesis that is less dependent on septin.

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“…In vivo, septin assembly is restricted both in time and in space through local activation of small GTPases such as Cdc42. Localized signaling leads to higher-order septin structures forming closely apposed to the plasma membrane at the plane of division, sites of polarity, and curved membranes (10,(12)(13)(14). Notably, eukaryotic cells of different geometries build higher-order septin assemblies of various shapes, sizes, and functions (4, 15, 16).…”

mentioning

confidence: 99%

Septin assemblies form by diffusion-driven annealing on membranes

Bridges

Zhang

Mehta

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

172

223

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Septins assemble into filaments and higher-order structures that act as scaffolds for diverse cell functions including cytokinesis, cell polarity, and membrane remodeling. Despite their conserved role in cell organization, little is known about how septin filaments elongate and are knitted together into higher-order assemblies. Using fluorescence correlation spectroscopy, we determined that cytosolic septins are in small complexes, suggesting that septin filaments are not formed in the cytosol. When the plasma membrane of live cells is monitored by total internal reflection fluorescence microscopy, we see that septin complexes of variable size diffuse in two dimensions. Diffusing septin complexes collide and make end-on associations to form elongated filaments and higher-order structures, an assembly process we call annealing. Septin assembly by annealing can be reconstituted in vitro on supported lipid bilayers with purified septin complexes. Using the reconstitution assay, we show that septin filaments are highly flexible, grow only from free filament ends, and do not exchange subunits in the middle of filaments. This work shows that annealing is a previously unidentified intrinsic property of septins in the presence of membranes and demonstrates that cells exploit this mechanism to build large septin assemblies.cytoskeleton | biophysics S eptin filaments form rings, bars, and gauzes that serve as a scaffold at cell division sites; act to retract blebbed regions of membrane; and restrict diffusion between cell compartments (1-4). Septin function is required for cell division and viability in many eukaryotes whereas misregulation is associated with cancers and neurodegenerative disorders (5-8). Furthermore, septins mediate entry of both bacterial and fungal pathogens into host cells (9-11). In vivo, septin assembly is restricted both in time and in space through local activation of small GTPases such as Cdc42. Localized signaling leads to higher-order septin structures forming closely apposed to the plasma membrane at the plane of division, sites of polarity, and curved membranes (10,(12)(13)(14). Notably, eukaryotic cells of different geometries build higher-order septin assemblies of various shapes, sizes, and functions (4, 15, 16). Although septins are critical for spatial organization of cell plasma membranes, their assembly and disassembly dynamics are not understood (15).Electron microscopy (EM) studies of recombinant and immunoprecipitated Saccharomyces cerevisiae septins have shown that septins form nonpolar hetero-octameric rod-shaped complexes in high-salt buffers (>300 mM) and elongated filaments when dialyzed into low-salt buffers (<100 mM) (17, 18). Structural analyses of worm and mammalian septins have revealed that the heteromeric, rod-shaped complex is conserved (19-21). Thus, septin rods characterized to date contain two copies of each septin subunit assembled into a nonpolar, heteromeric complex (Fig. S1). Association of purified septin proteins with phosphoinositide-containing membrane monola...

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Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility

Cited by 169 publications

References 37 publications

Septins 2, 7, and 9 and MAP4 co-localize along the axoneme in the primary cilium and control ciliary length

Septins 2, 7, and 9 and MAP4 co-localize along the axoneme in the primary cilium and control ciliary length

Sep(t)arate or not – how some cells take septin-independent routes through cytokinesis

Septin assemblies form by diffusion-driven annealing on membranes

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