Endolysosomal Cation Channels and Lung Disease

Abstract

Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease.

Keywords: BK; COPD; TRPA1; TRPM2; TRPML; TRPML3; TRPV2; asthma; cystic fibrosis; emphysema; lung injury.

Figure 1

Schematic of an alveolus showing expression of confirmed and putative endolysosomal/vesicular/LRO cation channels involved in lung physiology and disease in the different alveolar/lung cell types. Black labeled compartments represent nuclei.

Figure 2

(A) Single-cell suspension from murine whole lungs were analyzed using Drop-seq following 6 months of either filtered air (control) or cigarette smoke exposure (CS). The transcriptomes data are projected using the UMAP algorithm, each cell colour-coded by cell type, exposure condition and expression values of indicated genes. Cell types with prominent expression are highlighted. (B) The dotplot reflects normalized expression levels of selected genes across cell types. The dot colour indicates the expression level, and the dot size the percentage of cells expressing the gene per group. DC = dendritic cells; IM = interstitial macrophages; Mono = monocytes; AM = alveolar macrophages; Neutro = neutrophils; Baso = basophils; Ciliated = ciliated cells; Club and Goblet = Club (or clara) and Goblet cells; NK = natural killer cells; NEC = neuroendocrine cells; Fibro = fibroblasts; SMCs = smooth muscle cells; aCap = alveolar capillary; gCap = general capillary; VEC = vascular endothelial cells; LEC = lymphatic endothelial cells; AT1 and AT2 = alveolar epithelial cells type 1 and 2; MegaK = megakaryocytes.