Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases

Abstract

Edited by Luke O'NeillImpaired adenosine homeostasis has been associated with numerous human diseases. Lysosomes are referred to as the cellular recycling centers that generate adenosine by breaking down nucleic acids or ATP. Recent studies have suggested that lysosomal adenosine overload causes lysosome defects that phenocopy patients with mutations in transient receptor potential channel mucolipin-1 (TRPML1), a lysosomal Ca 2؉ channel, suggesting that lysosomal adenosine overload may impair TRPML1 and then lead to subsequent lysosomal dysfunction. In this study, we demonstrate that lysosomal adenosine is elevated by deleting adenosine deaminase (ADA), an enzyme responsible for adenosine degradation. We also show that lysosomal adenosine accumulation inhibits TRPML1, which is rescued by overexpressing ENT3, the adenosine transporter situated in the lysosome membrane. Moreover, ADA deficiency results in lysosome enlargement, alkalinization, and dysfunction. These are rescued by activating TRPML1. Importantly, ADA-deficient B-lymphocytes are more vulnerable to oxidative stress, and this was rescued by TRPML1 activation. Our data suggest that lysosomal adenosine accumulation impairs lysosome function by inhibiting TRPML1 and subsequently leads to cell death in B-lymphocytes. Activating TRPML1 could be a new therapeutic strategy for those diseases.

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

“…Thus, despite a current lack of data on remdesivir's ability to bind and subsequently, activate or inhibit any of the adenosine receptors, it is worth entertaining the possibility that, given its structural similarity to adenosine, remdesivir may potentially act as an A2a receptor antagonist, causing it to induce a transient NPC‐like cellular environment as part of its antiviral activity against SARS‐CoV‐2. In fact, several adenosine analogs have been previously shown to directly inhibit lysosomal activity in neutrophils, 95 as well as compete with intracellular adenosine on binding adenosine deaminase, an intra‐lysosomal adenosine‐metabolizing enzyme, 96 leading to the accumulation of adenosine within the lysosomal lumen 97 and inducing an LSD‐like cellular pathology with impaired regulation of lysosomal calcium stores 98 . Such features have all been previously shown to be part of the cytopathological findings in NPC 99 …”

Increased Lysosomal Exocytosis Induced by Lysosomal Ca2+ Channel Agonists Protects Human Dopaminergic Neurons from α-Synuclein Toxicity

“…5-1C, available at https://doi.org/10.1523/JNEUROSCI.3085-18.2019.f5-1). Pharmacological inhibition of TRPML1 was achieved by adding either 10 mM adenosine or 100 nM LaCl 3 in the culture media 1 h before TRPML1 activation (Dong et al, 2009;Zhong et al, 2017). Importantly, TRPML1 inhibition either by pretreatment with ei- (Figure legend continues.…”

Small Molecules for Early Endosome-Specific Patch Clamping

“…Dysfunction of the endolysosomal and autophagic system has also been implicated in the development of neurodegenerative diseases such as Parkinson's or Alzheimer's disease, metabolic, retinal and pigmentation disorders, infectious diseases, and cancer (Fraldi et al, 2016;Kondratskyi et al, 2013;Medina and Ballabio, 2015;Mole and Cotman, 2015;Saftig and Sandhoff, 2013;Sakurai et al, 2015;Venkatachalam et al, 2015;Zhang et al, 2009). Development and progression of diseases, including those mentioned above, have recently been found to be often associated with dysfunction of endolysosomal ion channels or transporters such as TRPML channels, two-pore channels, CLC transport proteins, or the BK channel (Zhang et al, 2009;Jentsch et al, 2010;Weinert et al, 2010;Stauber et al, 2012;Bae et al, 2014;Calcraft et al, 2009;Ruas et al, 2010;Chen et al, 2014;Grimm et al, 2014;Weinert et al, 2014;Hockey et al, 2015;Jentsch, 2015;Sakurai et al, 2015;Venkatachalam et al, 2015;De Leo et al, 2016;Favia et al, 2016;Kilpatrick et al, 2016;Zhong et al, 2016Zhong et al, , 2017Nguyen et al, 2017). In this context, it is also important to understand where the channels are functionally expressed, i.e., in early endosomes (EE) or late endosomes (LE), in lysosomes (LY), recycling endosomes (RE), autophagosomes, or lysosome-related organelles.…”