The septin cytoskeleton facilitates membrane retraction during motility and blebbing

Gilden, Julia; Peck, S.; Chen, Yi-Chun M.; Krummel, Matthew F.

doi:10.1083/jcb.201105127

Cited by 100 publications

(120 citation statements)

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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: 90%

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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Section: Non-canonical Functions Of Septins In Immune Cellsmentioning

confidence: 90%

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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“…Septins also form ring-like structures (septin rings) that regulate cell division, ciliogenesis, and neuronal synapses (65). SEPT2 is upregulated in renal cell carcinomas (67), which suggests that the upregulation of SEPT6 increases the SEPT2-SEPT6-SEPT7 filament and may play a role in tumorigenesis and/or metastasis (68)(69)(70), especially in VHL disease. However, the underlying molecular mechanism remains to be identified.…”

Section: Discussionmentioning

confidence: 99%

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Okumura

Uematsu

Byrne

et al. 2016

Molecular and Cellular Biology

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U biquitin-mediated proteolysis by the 26S proteasome plays an important role in the elimination of short-lived proteins (1), including those involved in cell cycle progression, cellular signaling in response to environmental stress or extracellular ligands, morphogenesis, secretion, DNA repair, and organelle biogenesis (2, 3). The pathway consists of two key steps, namely, the covalent attachment of multiple ubiquitin molecules to a target protein and the degradation of the ubiquitinated protein by the 26S proteasome complex. Several components act in concert to attach ubiquitin to a target protein, including a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein isopeptide ligase (E3). E3 is directly responsible for substrate recognition. On the basis of structural similarity, E3 enzymes are classified into three families: the HECT (homologous to E6-AP COOH terminus) family, the U-box family, and the RING finger-containing protein family.The elongin B and C-Cul2 or Cul5-SOCS box protein (ECS) family belongs to the cullin RING ligase (CRL) superfamily (4). pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a member of the ECS family. pVHL forms a complex with elongins B and C, Cul2, and the RING finger protein Rbx1 (5, 6). The CRL2 pVHL complex has ubiquitin ligase activity and targets the hypoxia-inducible factor ␣ (HIF-␣) family of transcription factors (HIF-1 to -3␣) for proteasomal degradation (7). At normal oxygen levels, proline residues in the LXXLAP sequence motif of HIF-␣ proteins are hydroxylated by three prolyl hydroxylases (PHD1 to -3), and an in-depth study revealed that PHD2 is a critical enzyme for the hydroxylation of HIF-1␣ (8, 9). Hydroxylated HIF-␣ is targeted by pVHL for polyubiquitination and proteasomal degradation (10-12). Under conditions of hypoxia (low oxygen level), HIF-␣ is not hydroxylated by PHDs and is therefore not recognized or targeted for degradation by pVHL. The unhydroxylated HIF-␣ dimerizes with constitutively expressed HIF-1␤, also known as an aryl hydrocarbon receptor nuclear translocator (ARNT), and translocates to the nucleus, where it induces the transcription of downstream target genes, including the genes coding for vascular endothelial growth factor A (VEGFA), solute carrier family 2 member 1 (SLC2A1; also known as GLUT1), and platelet-derived growth factor (PDGF) (13). Loss of functional pVHL protein prevents the O 2 -dependent degradation of HIF-␣, resulting in constitutive expression of HIF-dependent genes and VHL disease, which is characterized by a variety of lesions, including hemangioblastomas, renal clear cell carcinomas, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and papillary cystadenomas of the broad ligament (females) and epididymis (males) (13).Studies showing that heterozygous pVHL ϩ/Ϫ mice are phenotypically normal and VHL Ϫ/Ϫ mice die at embryonic day 10.5 (E10.5) to E12.5 (14), together with the existence of many pVHLinteracting proteins (13), a...

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“…In T-cells, septin knockdown results in abnormal cell morphology characterized by an increased frequency of blebs and extended cell protrusions (Fig. 2C) (63). Notably, septin influence on T-cell shape seems to occur as a response to malformed regions of the plasma membrane, rather than being proactive in preventing such deformations (63).…”

Section: Function Of Higher-order Structures At the Cell Cortexmentioning

confidence: 99%

Septin Form and Function at the Cell Cortex

Bridges

Gladfelter

2015

Journal of Biological Chemistry

129

138

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Septins are a conserved family of cytoskeletal GTP-binding proteins that function in cytokinesis, cell polarity, and membrane remodeling in many eukaryotic cell types (1, 2). To contribute to these diverse process, septins polymerize into filaments and higher-order structures that organize the cell cortex into domains that are tightly controlled in time and/or space (3). Higher-order septin structures act to recruit and/or integrate protein networks at specific locations, an example being contractile ring components in cell division (4 -7). In addition, septins are thought to alter lateral diffusion of proteins embedded in the plasma and endoplasmic reticulum (ER) 2 membranes and may influence local lipid composition (8 -10). In addition to membrane association, septins interact with, respond to, and organize the actin and microtubule cytoskeletons (11). Although septins were discovered by Hartwell, Pringle, and colleagues (12) in cell division cycle screens decades ago, understanding of septins has lagged behind other cytoskeletal systems. Recent biochemical, structural, and biophysical approaches, however, have made septins highly tractable and brought about exciting advances. Despite this recent progress, many fundamental questions remain in the septin field, in particular, the mechanisms by which septins associate with and influence the cell cortex.

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The septin cytoskeleton facilitates membrane retraction during motility and blebbing

Abstract: Septins assemble on the cortex and restore normal cell shape by retracting aberrantly protruding membranes and promoting cortical contraction during amoeboid motility.

Cited by 100 publications

References 48 publications

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

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

Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Septin Form and Function at the Cell Cortex

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