Natural isoaspartyl protein modification of ZAP70 alters T cell responses in lupus

Autor: Mei-Ling Yang, TuKiet T. Lam, Jean Kanyo, Insoo Kang, Zhaohui Sunny Zhou, Steven G. Clarke, Mark J. Mamula
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Autoimmunity, Vol 56, Iss 1 (2023)
Druh dokumentu: article
ISSN: 08916934
1607-842X
0891-6934
DOI: 10.1080/08916934.2023.2282945
Popis: AbstractProtein posttranslational modifications (PTMs) arise in a number of normal cellular biological pathways and in response to pathology caused by inflammation and/or infection. Indeed, a number of PTMs have been identified and linked to specific autoimmune responses and metabolic pathways. One particular PTM, termed isoaspartyl (isoAsp or isoD) modification, is among the most common spontaneous PTM occurring at physiological pH and temperature. Herein, we demonstrate that isoAsp modifications arise within the ZAP70 protein tyrosine kinase upon T-cell antigen receptor (TCR) engagement. The enzyme protein L-isoaspartate O-methyltransferase (PCMT1, or PIMT, EC 2.1.1.77) evolved to repair isoaspartyl modifications in cells. In this regard, we observe that increased levels of isoAsp modification that arise under oxidative stress are correlated with reduced PIMT activity in patients with systemic lupus erythematosus (SLE). PIMT deficiency leads to T cell hyper-proliferation and hyper-phosphorylation through ZAP70 signaling. We demonstrate that inducing the overexpression of PIMT can correct the hyper-responsive phenotype in lupus T cells. Our studies reveal a phenotypic role of isoAsp modification and phosphorylation of ZAP70 in lupus T cell autoimmunity and provide a potential therapeutic target through the repair of isoAsp modification.
Databáze: Directory of Open Access Journals
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