ArticleAnnals of the rheumatic diseases2022
Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.
Article in Annals of the rheumatic diseases, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Comparison of telitacicept and belimumab in systemic lupus erythematosus: a real-word retrospective study.Clinical rheumatology · 2026Article
- MAP4K2 suppresses antitumor immunity in a pancreatic cancer model by promoting Treg differentiation.The Journal of clinical investigation · 2026Article
- MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities.Experimental & molecular medicine · 2025Review
- The 330 risk loci known for systemic lupus erythematosus (SLE): a review.Frontiers in lupus · 2024Article
- DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated allergic inflammation by promoting nuclear export of Pur-α.The Journal of clinical investigation · 2023Article
- MRKNs: Gene, Functions, and Role in Disease and Infection.Frontiers in oncology · 2022Review
- MAP4K3/GLK inhibits Treg differentiation by direct phosphorylating IKKβ and inducing IKKβ-mediated FoxO1 nuclear export and Foxp3 downregulation.Theranostics · 2022Article
- BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus.Theranostics · 2021Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesMAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE.
methodsWe enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays.
resultsWe identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation.
conclusionsMultiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.
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