Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian Sibship

2009 ◽  
Vol 30 (5) ◽  
pp. E651-E661 ◽  
Author(s):  
Anne-Hélène Lebrun ◽  
Stephan Storch ◽  
Franz Rüschendorf ◽  
Mia-Lisa Schmiedt ◽  
Aija Kyttälä ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

124. Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

2009 ◽  
Vol 96 (2) ◽  
pp. S39
Author(s):  
Angela Schulz ◽  
Anne-Helene Lebrun ◽  
Stephan Storch ◽  
R∣schendorf Franz ◽  
Mia-Lisa Schmiedt ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship

2008 ◽  
Vol 39 (05) ◽  
Author(s):  
AH Lebrun ◽  
S Storch ◽  
A Kyttällä ◽  
SE Mole ◽  
A Kohlschütter ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Protein

scholarly journals CLN5 and CLN3 function as a complex to regulate endolysosome function

2021 ◽  
Author(s):  
Seda Yasa ◽  
Etienne Sauvageau ◽  
Graziana Modica ◽  
Stephane Lefrancois
Keyword(s):  
Membrane Protein ◽  
Neurodegenerative Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Integral Membrane Protein ◽  
Cytosolic Protein ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Sorting ◽  
Sorting Receptor ◽  
Lysosomal Protein ◽  
Endocytic Proteins

CLN5 is a soluble endolysosomal protein whose function is poorly understood. Mutations in this protein cause a rare neurodegenerative disease, Neuronal Ceroid Lipofuscinosis. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein, retromer, is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an endolysosomal integral membrane protein whose mutations also result in Neuronal Ceroid Lipofuscinosis, RAB7A, and a subset of RAB7A effectors. Our data supports a model where CLN3 and CLN5 function as an endolysosomal complex regulating various functions.

scholarly journals Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

2021 ◽  
Author(s):  
S. Devireddy ◽  
S.M. Ferguson
Keyword(s):  
Endoplasmic Reticulum ◽  
Frontotemporal Dementia ◽  
Lysosomal Storage Disease ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Efficient Delivery ◽  
Lysosomal Protein

AbstractProgranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interacts with prosaposin, another lysosomal protein, within the lumen of the endoplasmic reticulum (ER) and that prosaposin is required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates a network of interactions occurring early in the secretory pathway that promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

scholarly journals CLN5 and CLN3 function as a complex to regulate endolysosome function

2020 ◽  
Author(s):  
Seda Yasa ◽  
Etienne Sauvageau ◽  
Graziana Modica ◽  
Stephane Lefrancois
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Integral Membrane Protein ◽  
Common Pathway ◽  
Ceroid Lipofuscinosis ◽  
Lysosomal Sorting ◽  
Summary Statement ◽  
Sorting Receptor ◽  
Golgi Network ◽  
Lysosomal Protein

AbstractCLN5 is a soluble endolysosomal protein that regulates the itinerary of the lysosomal sorting receptor sortilin. Mutations in this protein cause neuronal ceroid lipofuscinosis, a rare neurodegenerative disorder, and have also been associated with Alzheimer’s disease, suggesting functional defects in a common pathway. We previously found that depletion of CLN5 leads to dysfunctional retromer, resulting in the degradation of the lysosomal sorting receptor, sortilin. However, how a soluble lysosomal protein can modulate the function of a cytosolic protein is not known. In this work, we show that deletion of CLN5 not only results in retromer dysfunction, but also in impaired endolysosome fusion events. This results in delayed degradation of endocytic proteins and in defective autophagy. CLN5 modulates these various pathways by regulating downstream interactions between CLN3, an integral membrane protein, Rab7A and a subset of Rab7A effectors. Mutations in CLN3 are also a cause of neuronal ceroid lipofuscinosis. Our data supports a model where CLN3 and CLN5 function as an endolysosome complex regulating several endosomal functions.Summary StatementWe have previously demonstrated that CLN3 is required for efficient endosome-to-trans Golgi Network (TGN) trafficking of sortilin by regulating retromer function. In this work, we show that CLN5, which interacts with CLN3, regulates retromer function by modulating key interactions between CLN3, Rab7A, retromer, and sortilin. Therefore, CLN3 and CLN5 serve as endosomal switch regulating the itinerary of the lysosomal sorting receptors.

Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo

2021 ◽  
Vol 221 (2) ◽  
Author(s):  
Swathi Devireddy ◽  
Shawn M. Ferguson
Keyword(s):  
Endoplasmic Reticulum ◽  
Frontotemporal Dementia ◽  
Lysosomal Storage Disease ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Efficient Delivery ◽  
Lysosomal Protein

Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia, while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

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