Aberrant HS1 molecule in a patient with systemic lupus erythematosus

Sawabe, Takuya; Horiuchi, Takahiko; Koga, Ritsuko; Tsukamoto, Hiroshi; Kojima, Takeshi; Harashima, Shin‐ichi; Kikuchi, Yuji; Otsuka, Junji; Mitoma, Hiroki; Yoshizawa, Shigeru; Niho, Yoshiyuki; Watanabe, Takeshi

doi:10.1038/sj.gene.6363932

Cited by 16 publications

(18 citation statements)

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“…These results suggest that this unique insertion-type polymorphism in HS1 accelerates signal transduction through BCR, which probably results in a lowered threshold of BCR triggering and dysregulation of the immune system, leading to the development of SLE. A recent study demonstrated another molecular defect in HS1 that transmits an accelerated signal through BCR in a patient with SLE (24). Taken together, these observations suggest that defects in HS1 function, as well as those in the molecules involved in BCR-mediated signal transduction, might be important factors in the pathogenesis of SLE.…”

Section: Discussionmentioning

confidence: 83%

“…The N-terminal 37-amino acid repeats can form a helix-turn-helix structure frequently found in the DNA binding domain of various transcription factors. Deletion of one of the 37-amino acid motifs was recently identified in a patient with SLE and was associated with increased apoptosis in WEHI-231 B lymphoma cells transfected with the mutant HS1 and in the patient's peripheral B lymphocytes (24). Because the 37-amino acid repeats are considered to be important in HS1 binding to F-actin (a cytoplasmic protein) in NIH313 cells (39), this mutant HS1 may display reduced binding to F-actin and thereby more easily translocate from cytoplasm to nucleus after BCR stimulation, accelerating signal transduction (40).…”

Section: Discussionmentioning

confidence: 95%

“…The constructs were linearized with Pvu I (Takara Shuzo), transfected into WEHI-231 cells by electroporation using a Gene Pulser apparatus (Bio-Rad, Hercules, CA) at 250V, 960 F, and selected in the presence of 1.0 mg/ml G418. Expression of the transfected cDNA was assessed by Western blot analysis and quantitative RT-PCR, as described previously (24,33).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, the patient's peripheral B lymphocytes displayed an increased level of apoptosis compared with those from control patients with SLE. This indicates that not only the quantitative decrease in the BCR signal-related molecules as in the case of Lyn and SHIP, but also the qualitative defect in the HS1 molecule are involved in the pathogenesis of human SLE (24).…”

mentioning

confidence: 93%

“…It is of particular interest that a defect in the hematopoietic cell-specific Lyn substrate 1 (HS1) molecule generated by exon skipping has been identified in a patient with SLE (24). HS1 is an important signaling molecule in BCR-mediated signal transduction (25)(26)(27)(28)(29).…”

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confidence: 99%

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Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cellspecific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE).Methods. The entire coding region of the HS1 gene was analyzed by reverse transcriptase-polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay.Results. We identified a glutamic acid-prolineglutamic acid-proline insertion between codons 366 and 367 (EPEP366-367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP؉ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P ‫؍‬ 0.016). The allele frequency of EPEP366-367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P ‫؍‬ 0.006). WEHI-231 cells transfected with EPEP؉ HS1 were 100-fold more sensitive to B cell receptor (BCR)-mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP؉ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion. These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the presence of a variety of autoantibodies. Various genetic and environmental factors, including B cell hyperactivity, T cell dysfunction, and cytokine dysregulation, initiate immune activation in SLE that culminates in organ inflammation and damage (1-9). It has been considered that B cells are innocent bystanders that are activated secondarily by autoreactive T lymphocytes. However, recent evidence from the study of human SLE and its murine models suggests that B lymphocytes are intrinsically defective and are primarily essential for the maintenance of activated/memory T cells by presenting antigens to T cells.B cells from mice deficient in Lyn (10-12), CD22 (13-16), SHP-1 (17,18) exhibit a hyperreactive phenotype and produce autoantibodies. Indeed, Lyn-deficient mice demonstrate activation of autoreactive B cells and subsequent SLE-like symptoms, such as the production of anti-double-stranded DNA (anti-dsDNA)

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Otsuka

Horiuchi

Yoshizawa

et al. 2004

Arthritis & Rheumatism

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Hematopoietic cell-specific lyn substrate (HCLS1 or HS1): A versatile actin-binding protein in leukocytes

Castro-Ochoa

Guerrero‐Fonseca

Schnoor

2018

Journal of Leukocyte Biology

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Leukocytes are constantly produced in the bone marrow and released into the circulation. Many different leukocyte subpopulations exist that exert distinct functions. Leukocytes are recruited to sites of inflammation and combat the cause of inflammation via many different effector functions. Virtually all of these processes depend on dynamic actin remodeling allowing leukocytes to adhere, migrate, phagocytose, and release granules. However, actin dynamics are not possible without actin‐binding proteins (ABP) that orchestrate the balance between actin polymerization, branching, and depolymerization. The homologue of the ubiquitous ABP cortactin in hematopoietic cells is hematopoietic cell‐specific lyn substrate‐1, often called hematopoietic cell‐specific protein‐1 (HCLS1 or HS1). HS1 has been reported in different leukocytes to regulate Arp2/3‐dependent migration. However, more evidence is emerging that HS1 functions go far beyond just being a direct actin modulator. For example, HS1 is important for the activation of GTPases and integrins, and mediates signaling downstream of many receptors including BCR, TCR, and CXCR4. In this review, we summarize current knowledge on HS1 functions and discuss them in a pathophysiologic context.

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Current advances in the human lupus genetics

Shen

Tsao

2004

Curr Rheumatol Rep

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Genetic predisposition has been firmly established as a key element in susceptibility to systemic lupus erythematosus (SLE). During the past three decades, association studies have assessed many genes for potential roles in predisposing to SLE. These studies have identified a few risk factors including hereditary deficiency of complement components, major histocompatibility complex class II alleles, and allelic variants for the Fc portion of IgG (FCGR) genes. In recent years, a few groups have completed linkage analyses in data sets from families containing multiple members affected with SLE. Results from these initial genome scans are encouraging; approximately eight chromosomal regions have been identified exhibiting evidence for significant linkage to SLE and have been confirmed using independent cohorts (1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12q24, and 16q12), suggesting the high likelihood of the presence of one or multiple SLE susceptibility genes at each locus. Another approach of linkage analyses conditioned on pedigrees where one affected member manifesting a particular clinical condition has also identified many chromosomal regions linked to SLE. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. Within 2q35-37, an intronic single nucleotide polymorphism (SNP) of the positional candidate gene program cell death 1 gene has been associated with SLE susceptibility. The SLE-associated SNP affects a transcription factor, RUNX1, binding site. Recently, SNPs of novel positional candidate genes that influence RUNX1 binding motifs have also been associated with other autoimmune diseases, suggesting the possibility of a common theme shared among susceptibility genes for autoimmune diseases. In the coming years, susceptibility genes responsible for the observed linkage will be identified, and will lead to further delineating genetic pathways involved in susceptibility to SLE.

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Aberrant HS1 molecule in a patient with systemic lupus erythematosus

Cited by 16 publications

References 60 publications

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis

Hematopoietic cell-specific lyn substrate (HCLS1 or HS1): A versatile actin-binding protein in leukocytes

Current advances in the human lupus genetics

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