Loss of mfsd8 alters the secretome during Dictyostelium aggregation

Huber, Robert J.; Gray, Joshua; Kim, William D.

doi:10.1016/j.ejcb.2023.151361

Cited by 2 publications

(12 citation statements)

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“…However, the lack of complete overlap of Cln5 with p80 in starved cells indicates that only a portion of extracellular Cln5 can be explained by lysosomal exocytosis. In addition, previous work showed that CtsD localizes extracellularly, as well as compartments of the endocytic pathway, including secretory lysosomes 29,30–32,36,37 . Thus, lysosomal exocytosis also likely contributes to the extracellular pool of CtsD.…”

Section: Discussionmentioning

confidence: 90%

“…Previous work in D. discoideum showed that Cln5 and CtsD are differentially secreted during the early stages of multicellular development 2,27,28,29, 30–32 . During this stage of the life cycle, autophagy pathways are activated to provide cells with nutrients and energy required for developmental processes 64 .…”

Section: Resultsmentioning

confidence: 99%

“…Like Cln5, CtsD localizes extracellularly, but is also found throughout the endocytic pathway 29,30,31,32,36,37 . While little is known about the pathways regulating the intracellular trafficking of CtsD, like Cln5, loss of cln3 or mfsd8 affects the release of CtsD from cells 29,30,31 …”

Section: Introductionmentioning

confidence: 99%

“…Homologs of human palmitoyl protein thioesterase 1 (PPT1/CLN1; D. discoideum Ppt1), tripeptidyl peptidase 1 (TPP1/CLN2; D. discoideum Tpp1B, Tpp1C, Tpp1F), CLN5 ( D. discoideum Cln5), and CTSD/CLN10 ( D. discoideum CtsD), as well as several cathepsin F (CTSF/CLN13)‐like proteins ( D. discoideum CprA, CprB, CprD, CprE, CprF, CprG, uncharacterized protein DDB0252831), are released from cells during D. discoideum development 2,27, 28–30, 31,32 . These findings are consistent with the presence of PPT1 and TPP1 in human saliva and the extracellular detection of CLN5, CTSD, and CTSF in mammalian systems 6–8,33–35 .…”

Section: Introductionmentioning

confidence: 99%

“…Cln5 is glycosylated and released from cells upon starvation via a pathway involving the CV system and at least two other CLN protein homologs, CLN3 (Cln3; CLN3 in humans) and major facilitator superfamily domain‐containing protein 8 (Mfsd8; MFSD8/CLN7 in humans) 2,27,29,30,32 . Like Cln5, CtsD localizes extracellularly, but is also found throughout the endocytic pathway 29,30,31,32,36,37 . While little is known about the pathways regulating the intracellular trafficking of CtsD, like Cln5, loss of cln3 or mfsd8 affects the release of CtsD from cells 29,30,31 …”

Section: Introductionmentioning

confidence: 99%

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Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD

Huber,

Kim,

Wilson‐Smillie

2024

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Ceroid lipofuscinosis neuronal 5 (CLN5) and cathepsin D (CTSD) are soluble lysosomal enzymes that also localize extracellularly. In humans, homozygous mutations in CLN5 and CTSD cause CLN5 disease and CLN10 disease, respectively, which are two subtypes of neuronal ceroid lipofuscinosis (commonly known as Batten disease). The mechanisms regulating the intracellular trafficking of CLN5 and CTSD and their release from cells are not well understood. Here, we used the social amoeba Dictyostelium discoideum as a model system to examine the pathways and cellular components that regulate the intracellular trafficking and release of the D. discoideum homologs of human CLN5 (Cln5) and CTSD (CtsD). We show that both Cln5 and CtsD contain signal peptides for secretion that facilitate their release from cells. Like Cln5, extracellular CtsD is glycosylated. In addition, Cln5 release is regulated by the amount of extracellular CtsD. Autophagy induction promotes the release of Cln5, and to a lesser extent CtsD. Release of Cln5 requires the autophagy proteins Atg1, Atg5, and Atg9, as well as autophagosomal‐lysosomal fusion. Atg1 and Atg5 are required for the release of CtsD. Together, these data support a model where Cln5 and CtsD are actively released from cells via their signal peptides for secretion and pathways linked to autophagy. The release of Cln5 and CtsD from cells also requires microfilaments and the D. discoideum homologs of human AP‐3 complex mu subunit, the lysosomal‐trafficking regulator LYST, mucopilin‐1, and the Wiskott–Aldrich syndrome‐associated protein WASH, which all regulate lysosomal exocytosis in this model organism. These findings suggest that lysosomal exocytosis also facilitates the release of Cln5 and CtsD from cells. In addition, we report the roles of ABC transporters, microtubules, osmotic stress, and the putative D. discoideum homologs of human sortilin and cation‐independent mannose‐6‐phosphate receptor in regulating the intracellular/extracellular distribution of Cln5 and CtsD. In total, this study identifies the cellular mechanisms regulating the release of Cln5 and CtsD from D. discoideum cells and provides insight into how altered trafficking of CLN5 and CTSD causes disease in humans.

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Section: Discussionmentioning

confidence: 90%