The amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocytic lysosome reformation

Gan, Qiwen; Wang, Xin; Zhang, Qian; Yin, Qiuyuan; Jian, Youli; Liu, Yubing; Xuan, Nan; Li, Jinglin; Zhou, Junpei; Li, Kai; Jing, Yudong; Wang, Xiaochen; Yang, Chonglin

doi:10.1083/jcb.201901074

Cited by 23 publications

(16 citation statements)

References 63 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further prove the idea that the accumulation of enlarged ALs can activate TOR, we knocked down ALR genes, including slc-36.1 and ppk-3 49 , which leads to enlarged ALs (Supplementary Fig. 7d ).…”

Section: Resultsmentioning

confidence: 99%

Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

et al. 2021

View full text Add to dashboard Cite

The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.

show abstract

Section: Resultsmentioning

confidence: 99%

Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Low PtdIns(3,5)P 2 levels causes multiple defects including impaired autophagic flux, nutrient recycling, and phagosome resolution [ 10 , 27 ]. These defects are likely derived from the inability of lysosomes to reform or separate after fusion with other lysosomes, late endosomes, phagosomes, and autolysosomes [ 4 , 10 , 30 , 67 , 68 ]. As a corollary, lysosomes coalesce to become larger but fewer [ 4 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

et al. 2021

View full text Add to dashboard Cite

Lysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves, endosomes, phagosomes, and autophagosomes. Lysosome number and size depends on balanced fusion and fission rates. Thus, conditions that favour fusion over fission can reduce lysosome numbers while enlarging their size. Conversely, favouring fission over fusion may cause lysosome fragmentation and increase their numbers. PIKfyve is a phosphoinositide kinase that generates phosphatidylinositol-3,5-bisphosphate to modulate lysosomal functions. PIKfyve inhibition causes an increase in lysosome size and reduction in lysosome number, consistent with lysosome coalescence. This is thought to proceed through reduced lysosome reformation and/or fission after fusion with endosomes or other lysosomes. Previously, we observed that photo-damage during live-cell imaging prevented lysosome coalescence during PIKfyve inhibition. Thus, we postulated that lysosome fusion and/or fission dynamics are affected by reactive oxygen species (ROS). Here, we show that ROS generated by various independent mechanisms all impaired lysosome coalescence during PIKfyve inhibition and promoted lysosome fragmentation during PIKfyve re-activation. However, depending on the ROS species or mode of production, lysosome dynamics were affected distinctly. H2O2 impaired lysosome motility and reduced lysosome fusion with phagosomes, suggesting that H2O2 reduces lysosome fusogenecity. In comparison, inhibitors of oxidative phosphorylation, thiol groups, glutathione, or thioredoxin, did not impair lysosome motility but instead promoted clearance of actin puncta on lysosomes formed during PIKfyve inhibition. Additionally, actin depolymerizing agents prevented lysosome coalescence during PIKfyve inhibition. Thus, we discovered that ROS can generally prevent lysosome coalescence during PIKfyve inhibition using distinct mechanisms depending on the type of ROS.

show abstract

“…Meanwhile, at the mammalian lysosome, SLC38A9 is an amino acid transporter that associates with mTORC1 regulatory machinery and communicates the abundance of arginine, lysine, and leucine to this signaling pathway (Jung et al, 2015; Rebsamen et al, 2015; Wang et al, 2015). Another recently reported example of an amino acid transporter with additional functions conferred by an interacting protein is PAT1 (also known as LYAAT-1 and SLC36A1), whose interaction with the PPK-3/PIKfyve lipid kinase is critical for the lysosomal degradation of phagocytic substrates in C. elegans (Gan et al, 2019). Our new data support the inclusion of PQLC2 into the subset of transporters that have the ability to perform a second function.…”

Section: Discussionmentioning

confidence: 99%

PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

Amick

Tharkeshwar

Talaia

et al. 2019

Journal of Cell Biology

View full text Add to dashboard Cite

The C9orf72 protein is required for normal lysosome function. In support of such functions, C9orf72 forms a heterotrimeric complex with SMCR8 and WDR41 that is recruited to lysosomes when amino acids are scarce. These properties raise questions about the identity of the lysosomal binding partner of the C9orf72 complex and the amino acid–sensing mechanism that regulates C9orf72 complex abundance on lysosomes. We now demonstrate that an interaction with the lysosomal cationic amino acid transporter PQLC2 mediates C9orf72 complex recruitment to lysosomes. This is achieved through an interaction between PQLC2 and WDR41. The interaction between PQLC2 and the C9orf72 complex is negatively regulated by arginine, lysine, and histidine, the amino acids that PQLC2 transports across the membrane of lysosomes. These results define a new role for PQLC2 in the regulated recruitment of the C9orf72 complex to lysosomes and reveal a novel mechanism that allows cells to sense and respond to changes in the availability of cationic amino acids within lysosomes.

show abstract

The amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocytic lysosome reformation

Cited by 23 publications

References 63 publications

Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans

Reactive oxygen species prevent lysosome coalescence during PIKfyve inhibition

PQLC2 recruits the C9orf72 complex to lysosomes in response to cationic amino acid starvation

Contact Info

Product

Resources

About