-
Nature Genetics Jul 2021SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal...
SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.
Topics: Animals; Genes, Dominant; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Heterozygote; Humans; Mice; Neurodevelopmental Disorders; Phenotype; Spectrin
PubMed: 34211179
DOI: 10.1038/s41588-021-00886-z -
Nature Structural & Molecular Biology Jul 2022The stability and shape of the erythrocyte membrane is provided by the ankyrin-1 complex, but how it tethers the spectrin-actin cytoskeleton to the lipid bilayer and the...
The stability and shape of the erythrocyte membrane is provided by the ankyrin-1 complex, but how it tethers the spectrin-actin cytoskeleton to the lipid bilayer and the nature of its association with the band 3 anion exchanger and the Rhesus glycoproteins remains unknown. Here we present structures of ankyrin-1 complexes purified from human erythrocytes. We reveal the architecture of a core complex of ankyrin-1, the Rhesus proteins RhAG and RhCE, the band 3 anion exchanger, protein 4.2, glycophorin A and glycophorin B. The distinct T-shaped conformation of membrane-bound ankyrin-1 facilitates recognition of RhCE and, unexpectedly, the water channel aquaporin-1. Together, our results uncover the molecular details of ankyrin-1 association with the erythrocyte membrane, and illustrate the mechanism of ankyrin-mediated membrane protein clustering.
Topics: Anion Exchange Protein 1, Erythrocyte; Ankyrins; Cytoskeletal Proteins; Erythrocyte Membrane; Erythrocytes; Humans; Spectrin
PubMed: 35835865
DOI: 10.1038/s41594-022-00792-w -
Developmental Cell Aug 2019The Hippo signaling pathway regulates diverse physiological processes, and its dysfunction has been implicated in an increasing number of human diseases, including... (Review)
Review
The Hippo signaling pathway regulates diverse physiological processes, and its dysfunction has been implicated in an increasing number of human diseases, including cancer. Here, we provide an updated review of the Hippo pathway; discuss its roles in development, homeostasis, regeneration, and diseases; and highlight outstanding questions for future investigation and opportunities for Hippo-targeted therapies.
Topics: Animals; Cell Cycle Proteins; Exosome Multienzyme Ribonuclease Complex; Gene Expression Regulation, Developmental; Humans; Neoplasms; Signal Transduction; Transcription Factors
PubMed: 31386861
DOI: 10.1016/j.devcel.2019.06.003 -
Nature Immunology Jun 2023Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T...
Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8 T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of βII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1-βII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Movement; Immunotherapy, Adoptive; Lymphocyte Function-Associated Antigen-1; Receptors, Chimeric Antigen; Spectrin; Humans; Female
PubMed: 37069398
DOI: 10.1038/s41590-023-01498-x -
Cells Aug 2022Cytoskeletal spectrin is found in (non)erythroid cells. Eukaryotic endocytosis takes place for internalizing cargos from extracellular milieu. The role of spectrin in... (Review)
Review
Cytoskeletal spectrin is found in (non)erythroid cells. Eukaryotic endocytosis takes place for internalizing cargos from extracellular milieu. The role of spectrin in endocytosis still remains poorly understood. Here, I summarize current knowledge of spectrin function, spectrin-based cytoskeleton and endocytosis of erythrocytes, and highlight how spectrin contributes to endocytosis and working models in different types of cells. From an evolutionary viewpoint, I discuss spectrin and endocytosis in a range of organisms, particularly in plants and yeast where spectrin is absent. Together, the role of spectrin in endocytosis is related to its post-translational modification, movement/rearrangement, elimination (by proteases) and meshwork fencing.
Topics: Cytoskeleton; Endocytosis; Erythrocytes; Membrane Proteins; Spectrin
PubMed: 35954302
DOI: 10.3390/cells11152459 -
Cell Apr 2023The spectrin-based membrane skeleton is a ubiquitous membrane-associated two-dimensional cytoskeleton underneath the lipid membrane of metazoan cells. Mutations of...
The spectrin-based membrane skeleton is a ubiquitous membrane-associated two-dimensional cytoskeleton underneath the lipid membrane of metazoan cells. Mutations of skeleton proteins impair the mechanical strength and functions of the membrane, leading to several different types of human diseases. Here, we report the cryo-EM structures of the native spectrin-actin junctional complex (from porcine erythrocytes), which is a specialized short F-actin acting as the central organizational unit of the membrane skeleton. While an α-/β-adducin hetero-tetramer binds to the barbed end of F-actin as a flexible cap, tropomodulin and SH3BGRL2 together create an absolute cap at the pointed end. The junctional complex is strengthened by ring-like structures of dematin in the middle actin layers and by patterned periodic interactions with tropomyosin over its entire length. This work serves as a structural framework for understanding the assembly and dynamics of membrane skeleton and offers insights into mechanisms of various ubiquitous F-actin-binding factors in other F-actin systems.
Topics: Animals; Humans; Actin Cytoskeleton; Actins; Cytoskeleton; Erythrocytes; Spectrin; Swine
PubMed: 37044097
DOI: 10.1016/j.cell.2023.03.017 -
Current Biology : CB May 2021Lindsay Teliska and Matthew Rasband introduce spectrins - cytoskeletal proteins that localise to the inner face of the plasma membrane and serve a scaffolding function...
Lindsay Teliska and Matthew Rasband introduce spectrins - cytoskeletal proteins that localise to the inner face of the plasma membrane and serve a scaffolding function between membrane proteins and the actin cortex.
Topics: Actins; Cell Membrane; Membrane Proteins; Spectrin
PubMed: 34033780
DOI: 10.1016/j.cub.2021.01.040 -
Science Advances Mar 2023Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition...
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti-βII-spectrin IgA. As in patients with IgAN, IgA plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.
Topics: Mice; Animals; Glomerulonephritis, IGA; Mesangial Cells; Spectrin; Immunoglobulin A; Autoantibodies
PubMed: 36947618
DOI: 10.1126/sciadv.add6734 -
Movement Disorders : Official Journal... Jun 2022Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability,...
BACKGROUND
Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.
OBJECTIVES
We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.
METHODS
We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.
RESULTS
We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.
CONCLUSIONS
We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.
Topics: Carrier Proteins; Cerebellar Ataxia; Humans; Intellectual Disability; Microfilament Proteins; Mutation; Paraplegia; Pedigree; Phenotype; Spastic Paraplegia, Hereditary; Spectrin
PubMed: 35150594
DOI: 10.1002/mds.28959