Equilibrative Nucleoside Transporter 3 Regulates T Cell Homeostasis by Coordinating Lysosomal Function with Nucleoside Availability

Abstract

T cells are a versatile immune cell population responding to challenges by differentiation and proliferation followed by contraction and memory formation. Dynamic metabolic reprogramming is essential for T cells to meet the biosynthetic needs and the reutilization of biomolecules, processes that require active participation of metabolite transporters. Here, we show that equilibrative nucleoside transporter 3 (ENT3) is highly expressed in peripheral T cells and has a key role in maintaining T cell homeostasis by supporting the proliferation and survival of T cells. ENT3 deficiency leads to an enlarged and disturbed lysosomal compartment, resulting in accumulation of surplus mitochondria, elevation of intracellular reactive oxygen species, and DNA damage in T cells. Our results identify ENT3 as a vital metabolite transporter that supports T cell homeostasis and activation by regulating lysosomal integrity and the availability of nucleosides. Moreover, we uncovered that T cell lysosomes are an important source of salvaged metabolites for survival and proliferation.

Single-Nucleotide Polymorphisms Related to Leprosy Risk and Clinical Phenotypes Among Chinese Population

“…27 Previous study suspects that the ENT3 protein is highly expressed in peripheral T cells and has a key role in maintaining T cell homeostasis by supporting the proliferation and survival of T cells. 28 Our data provide evidence for the possibility of ENT3 affect the final outcome of the response towards an infecting pathogen by influencing the host's immunologic status. SNP rs3764147 in LACC1 shows significant association with leprosy susceptibility and its reactive status in our study.…”

Entosis is induced by ultraviolet radiation

“…While we show here that UV-irradiated cells also have a survival advantage that is linked to entosis, whether metabolite scavenging underlies the enhanced survival of entotic cells remains to be determined. Significant nucleotide pools are known to be needed for DNA repair following UV radiation, and the sizes of nucleotide pools can be rate limiting for cell survival ( Wei et al., 2018 ), suggesting that the scavenging of nucleotides could plausibly underlie the observed survival advantage of engulfing cells. Alternatively, it is possible that cells with low levels of stress signaling, which are spared entotic death, may have related survival advantages to other forms of cell death as well, and that intrinsic stress resistance contributes to survival.…”

Autoinflammatory characteristics and short-term effects of delivering high-dose steroids to the surface of the intact endolymphatic sac and incus in refractory Ménière's disease

“…SLC29A3 mRNA expression has also been detected in the inner ear of mouse embryo (Morgan et al., 2010). hENT3 regulates T cell homeostasis by coordinating lysosomal function with nucleoside availability (Wei et al., 2018), and hENT3 spectrum disorder impairs nucleoside transport, protein localization, and stability (Kang et al., 2010). The patients display symptoms such as cutaneous hyperpigmentation, hypertrichosis, cardiac abnormalities, hearing loss, hepatomegaly hypogonadism, and pigmented hypertrichotic dermatosis with insulin-dependent diabetes (Kang et al., 2010).…”