The lysosomal enzyme receptor protein (LERP) is not essential, but is implicated in lysosomal function in<i>Drosophila melanogaster</i>

Hasanagic, Medina; Meel, Eline van; Luan, Shan; Aurora, Rajeev; Kornfeld, Stuart; Eissenberg, Joel C.

doi:10.1242/bio.013334

Cited by 18 publications

(9 citation statements)

References 22 publications

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“…Without recycling of CI-M6PR, lysosomal hydrolases are not efficiently delivered, resulting in lysosomal dysfunction ( McMillan et al, 2017 ). To test whether lysosomal dysfunction results in accumulation of mucin cargo proteins within endosomes, we looked for retention of mucins in loss-of-function Lerp (the fly ortholog of CI-M6PR ) mutant cells ( Hasanagic et al, 2015 ). Importantly, Lerp mutant salivary glands did not contain any mucin cargo proteins at the onset of metamorphosis ( …”

Section: Resultsmentioning

confidence: 99%

Mistargeting of secretory cargo in retromer-deficient cells

Neuman

Terry

Selegue

et al. 2021

Disease Models &Amp; Mechanisms

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Intracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process is especially demanding in professional secretory cells, which synthesize and secrete massive quantities of cargo proteins via regulated exocytosis. The Drosophila larval salivary glands are composed of professional secretory cells that synthesize and secrete mucin proteins at the onset of metamorphosis. Using the larval salivary glands as a model system, we have identified a role for the highly conserved retromer complex in trafficking of secretory granule membrane proteins. We demonstrate that retromer-dependent trafficking via endosomal tubules is induced at the onset of secretory granule biogenesis, and that recycling via endosomal tubules is required for delivery of essential secretory granule membrane proteins to nascent granules. Without retromer function, nascent granules do not contain the proper membrane proteins; as a result, cargo from these defective granules is mistargeted to Rab7-positive endosomes, where it progressively accumulates to generate dramatically enlarged endosomes. Retromer complex dysfunction is strongly associated with neurodegenerative diseases, including Alzheimer's disease, characterized by accumulation of amyloid β (Aβ). We show that ectopically expressed amyloid precursor protein (APP) undergoes regulated exocytosis in salivary glands and accumulates within enlarged endosomes in retromer-deficient cells. These results highlight recycling of secretory granule membrane proteins as a critical step during secretory granule maturation and provide new insights into our understanding of retromer complex function in secretory cells. These findings also suggest that missorting of secretory cargo, including APP, may contribute to the progressive nature of neurodegenerative disease.

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Section: Resultsmentioning

confidence: 99%

Mistargeting of secretory cargo in retromer-deficient cells

Neuman

Terry

Selegue

et al. 2021

Disease Models &Amp; Mechanisms

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show abstract

“…Notably, the single MPR orthologue identified in D . melanogaster , named lysosomal enzyme receptor protein (LERP) [ 61 ], lacks the residues critical for mannose 6-phosphate binding and it contributes only moderately to lysosomal enzyme targeting [ 62 ]. This may explain why two of the key lysine residues (K183 and K214), and the tyrosine one, are not conserved in AtAGA and LhAGA.…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization and comparison of aspartylglucosaminidases secreted in venom of the parasitoid wasps Asobara tabida and Leptopilina heterotoma

et al. 2017

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Aspartylglucosaminidase (AGA) is a low-abundance intracellular enzyme that plays a key role in the last stage of glycoproteins degradation, and whose deficiency leads to human aspartylglucosaminuria, a lysosomal storage disease. Surprisingly, high amounts of AGA-like proteins are secreted in the venom of two phylogenetically distant hymenopteran parasitoid wasp species, Asobara tabida (Braconidae) and Leptopilina heterotoma (Cynipidae). These venom AGAs have a similar domain organization as mammalian AGAs. They share with them key residues for autocatalysis and activity, and the mature α- and β-subunits also form an (αβ)2 structure in solution. Interestingly, only one of these AGAs subunits (α for AtAGA and β for LhAGA) is glycosylated instead of the two subunits for lysosomal human AGA (hAGA), and these glycosylations are partially resistant to PGNase F treatment. The two venom AGAs are secreted as fully activated enzymes, they have a similar aspartylglucosaminidase activity and are both also efficient asparaginases. Once AGAs are injected into the larvae of the Drosophila melanogaster host, the asparaginase activity may play a role in modulating their physiology. Altogether, our data provide new elements for a better understanding of the secretion and the role of venom AGAs as virulence factors in the parasitoid wasps’ success.

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“…Without recycling of CI-M6PR, lysosomal hydrolases are not efficiently delivered, resulting in lysosomal dysfunction (McMillan et al, 2017). To test whether lysosomal dysfunction results in accumulation of mucin cargo proteins within endosomes, we looked for retention of mucins in loss-of-function Lerp (the fly ortholog of CI-M6PR) mutant cells (Hasanagic et al, 2015).…”

Section: Mistargeting Of Secretory Cargo Proteins To Endosomes Beginsmentioning

confidence: 99%

Mistargeting of secretory cargo in retromer-deficient cells

Neuman

Terry

Selegue

et al. 2020

Preprint

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ABSTRACTIntracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process is especially demanding in professional secretory cells, which synthesize and secrete massive quantities of cargo proteins via regulated exocytosis. The Drosophila larval salivary glands are professional secretory cells that synthesize and secrete mucin proteins at the onset of metamorphosis. Using the larval salivary glands as a model system, we have identified a role for the highly conserved retromer complex in trafficking of secretory granule membrane proteins. We demonstrate that retromer-dependent trafficking via endosomal tubules is induced at the onset of secretory granule biogenesis, and that recycling via endosomal tubules is required for delivery of essential secretory granule membrane proteins to nascent granules. Without retromer function, nascent granules do not contain the proper membrane proteins; as a result, cargo from these defective granules is mistargeted to Rab7-positive endosomes, where it progressively accumulates to generate dramatically enlarged endosomes. Retromer complex dysfunction is strongly associated with Alzheimer’s disease, characterized by accumulation of amyloid β (Aβ). We show that amyloid precursor protein (APP) undergoes regulated exocytosis and accumulates within enlarged endosomes in retromer-deficient cells. These results highlight recycling of secretory granule membrane proteins as a critical step during secretory granule maturation and provide new insights into our understanding of retromer complex function in secretory cells. Our data also suggests that misrouting of secretory cargo, including APP, may contribute to the progressive nature of neurodegenerative disease.SUMMARY STATEMENTRetromer complex dysfunction is implicated in neurodegeneration. Here the authors show a new role for the retromer complex in recycling of secretory membrane and cargo proteins during regulated exocytosis.

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The lysosomal enzyme receptor protein (LERP) is not essential, but is implicated in lysosomal function inDrosophila melanogaster

Cited by 18 publications

References 22 publications

Mistargeting of secretory cargo in retromer-deficient cells

Mistargeting of secretory cargo in retromer-deficient cells

Biochemical characterization and comparison of aspartylglucosaminidases secreted in venom of the parasitoid wasps Asobara tabida and Leptopilina heterotoma

Mistargeting of secretory cargo in retromer-deficient cells

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