Martin Amandine, Caron Solène, Marcotte Mélissa, Bronnec Pauline, Garneret Etienne, Martel Nora, Maalouf Georgina, Sève Pascal, Saadoun David, Jamilloux Yvan, Henry Thomas
CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, University Lyon, F-69007 Lyon, France.
CeRéMAIA: Centre National de Références Maladies Autoinflammatoires et Amylose Inflammatoire, 69000 Lyon, France.
iScience. 2024 Dec 10;28(1):111563. doi: 10.1016/j.isci.2024.111563. eCollection 2025 Jan 17.
Alpha-kinase 1 (ALPK1) is an immune receptor sensing the bacterial nucleotide sugar ADP-heptose. ALPK1 phosphorylates TIFA leading to its oligomerization and downstream NF-κB activation. Specific mutations in are associated with an autoinflammatory syndrome termed ROSAH and with spiradenoma (skin cancers with sweat gland differentiation). This study investigated ALPK1 responses in human mononuclear cells and demonstrates that human mononuclear cells have distinct abilities to respond to ADP-heptose. Notably, IFN-γ is required to license the ALPK1/TIFA pathway in monocytes, while it was dispensable for the responsiveness of B cells. IFN-γ induced upregulation in monocytes, and induction was sufficient to recapitulate the licensing effect of IFN-γ. IFN-γ treatment promoted the phenotypic expression of pathogenic mutations. The licensing effect of IFN-γ in monocytes was blocked by JAK inhibitors. These findings underscore the critical role of IFN-γ in ALPK1 function and suggest JAK inhibitors as potential therapies for ALPK1-related inflammatory conditions.
α激酶1（ALPK1）是一种可感知细菌核苷酸糖ADP-庚糖的免疫受体。ALPK1使TIFA磷酸化，导致其寡聚化并激活下游的核因子κB。ALPK1的特定突变与一种名为ROSAH的自身炎症综合征以及汗腺螺旋腺瘤（具有汗腺分化的皮肤癌）相关。本研究调查了人类单核细胞中ALPK1的反应，并证明人类单核细胞对ADP-庚糖具有不同的反应能力。值得注意的是，单核细胞中激活ALPK1/TIFA途径需要γ干扰素，而它对于B细胞的反应性是可有可无的。γ干扰素诱导单核细胞中 上调，并且 诱导足以重现γ干扰素的许可作用。γ干扰素治疗促进了致病性 突变的表型表达。γ干扰素在单核细胞中的许可作用被JAK抑制剂阻断。这些发现强调了γ干扰素在ALPK1功能中的关键作用，并表明JAK抑制剂可作为治疗ALPK1相关炎症性疾病的潜在疗法。
