Wernet Nicole D, Tecle Eillen, Sarmiento Mario Bardan, Kuo Cheng-Ju, Chhan Crystal B, Baick Ian, Batachari Lakshmi E, Franklin Latisha, Herneisen Alice, Bhabha Gira, Ekiert Damian C, Hanna-Rose Wendy, Troemel Emily R
School of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
iScience. 2025 Feb 3;28(3):111950. doi: 10.1016/j.isci.2025.111950. eCollection 2025 Mar 21.
Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are enzymes in the purine salvage pathway, which recycles purines to meet cellular demands. Mutations of these enzymes in humans cause inflammatory and immunodeficiency syndromes, but the mechanisms are not well understood. Prior work in the nematode demonstrated that loss of PNP ortholog PNP-1 induced an immune response called the intracellular pathogen response (IPR). Here, we show that loss of the enzyme upstream of PNP-1 called ADAH-1 (ADA homolog) also induces the IPR and promotes resistance against intracellular pathogens. Unlike PNP-1, ADAH-1 is essential for organismal development. Importantly, we find that supplementation of deoxyadenosine, a substrate for ADA, induces the IPR and promotes resistance to intracellular pathogens in , a finding we extend to human cells. Thus, mutations in ADA and PNP induce innate immunity through increased deoxyadenosine, a phenomenon that is conserved from to humans.
腺苷脱氨酶（ADA）和嘌呤核苷磷酸化酶（PNP）是嘌呤补救途径中的酶，该途径可回收嘌呤以满足细胞需求。人类中这些酶的突变会导致炎症和免疫缺陷综合征，但其机制尚不清楚。之前在秀丽隐杆线虫中的研究表明，PNP直系同源物PNP-1的缺失会引发一种名为细胞内病原体反应（IPR）的免疫反应。在此，我们表明，PNP-1上游的酶ADAH-1（ADA同源物）的缺失也会诱导IPR，并增强对细胞内病原体的抵抗力。与PNP-1不同，ADAH-1对生物体发育至关重要。重要的是，我们发现补充ADA的底物脱氧腺苷会诱导IPR，并增强秀丽隐杆线虫对细胞内病原体的抵抗力，这一发现我们也扩展到了人类细胞。因此，ADA和PNP中的突变通过增加脱氧腺苷来诱导先天免疫，这一现象从秀丽隐杆线虫到人类都是保守的。
