A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Bajaj, Lakshya; Sharma, Jaiprakash; Ronza, Alberto di; Zhang, Pengcheng; Eblimit, Aiden; Pal, Rituraj; Roman, Dany; Collette, John R.; Booth, Clarissa D.; Chang, K. T.; Sifers, Richard N.; Jung, Sung Yun; Weimer, Jill M.; Chen, Rui; Schekman, Randy; Sardiello, Marco

doi:10.1172/jci130955

Cited by 47 publications

(80 citation statements)

References 80 publications

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“…Thus, although it has previously been proposed that a process of bulk flow mediates the egress of many lumenal proteins from the ER, progranulin and prosaposin are particularly dependent on Surf4 for their export. This dependence of progranulin and prosaposin on Surf4 parallels (but is distinct from) other recent reports of lysosomal hydrolases relying on CLN6 and CLN8 proteins for their ER export 23,24 . Beyond defining a critical step in the intracellular traffic of progranulin and prosaposin, this study sheds light on how the sorting of cargoes is coordinated between organelles and has implications for therapeutic strategies designed to increase progranulin levels as a therapy for frontotemporal dementia arising from its deficiency.…”

Section: Discussionsupporting

confidence: 83%

“…Our discovery of a role for Surf4 in promoting the ER exit of progranulin and prosaposin parallels recent studies that have identified roles for CLN6 and CLN8 proteins in the sorting of other lysosomal proteins at the ER 23,24 . Like mutations in the GRN gene, CLN6 and CLN8 mutations also cause the lysosome storage disease known as neuronal ceroid lipofuscinosis 36,37 .…”

Section: Discussionsupporting

confidence: 73%

“…Collectively, these quantitative analyses of the dynamic trafficking of prosaposin and progranulin establish a critical role for Surf4 in their delivery from the ER to the Golgi. Notably, ~6.6 fold reduction in the ER to Golgi traffic of prosaposin-RUSH in Surf4 KO cells stands out compared to what has been reported for other Surf4-dependent cargos and CLN6/CLN8 dependent lysosomal hydrolase cargos 23,[25][26][27] . This demonstrates the major extent to which Surf4 prioritizes the ER export of prosaposin (and by extension progranulin).…”

Section: Surf4 Is Required For the Efficient Er Exit Of Prosaposin Anmentioning

confidence: 65%

“…Of these, ERGIC-53 and Surf4 are best characterized for their ability to promote the ER export of lumenal proteins. More recently CLN6 was shown to recruit some lysosomal enzymes and present them to CLN8 for ER export 23,24 . However, we ruled out a requirement for CLN6/CLN8 in the trafficking of progranulin based on our observation of normal lysosome localization of progranulin in fibroblasts from the nclf mutant mouse that lacks CLN6 (Supp.…”

Section: Resultsmentioning

confidence: 99%

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

Devireddy

Ferguson

2021

Preprint

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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 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.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 73%

Section: Surf4 Is Required For the Efficient Er Exit Of Prosaposin Anmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

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

Devireddy

Ferguson

2021

Preprint

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“…In addition, UGGT1 and UGGT2 may reside in separate subdomains within the ER, and this could contribute to substrate accessibility. The CLN6/CLN8 transmembrane complex appears to recognize lysosomal proteins within the ER for COPII packaging in support of a possible mechanism of lysosomal substrate selection ( Bajaj et al, 2020 ). An additional possibility addressed was that the level of expression of the lysosomal proteins identified as UGGT2 substrates may be augmented in ALG6/UGGT1 -/- cells.…”

Section: Discussionmentioning

confidence: 99%

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Adams

Canniff

Guay

et al. 2020

eLife

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UDP-glucose:glycoprotein glucosyltransferase (UGGT) 1 and 2 are central hubs in the chaperone network of the endoplasmic reticulum (ER), acting as gatekeepers to the early secretory pathway, yet little is known about their cellular clients. These two quality control sensors control lectin chaperone binding and glycoprotein egress from the ER. A quantitative glycoproteomics strategy was deployed to identify cellular substrates of the UGGTs at endogenous levels in CRISPR-edited HEK293 cells. The 71 UGGT substrates identified were mainly large multidomain and heavily glycosylated proteins when compared to the general N-glycoproteome. UGGT1 was the dominant glucosyltransferase with a preference toward large plasma membrane proteins whereas UGGT2 favored the modification of smaller, soluble lysosomal proteins. This study sheds light on differential specificities and roles of UGGT1 and UGGT2 and provides insight into the cellular reliance on the carbohydrate-dependent chaperone system to facilitate proper folding and maturation of the cellular N-glycoproteome.

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Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Mitchell

Russell

Barrell

et al. 2023

Developmental Neurobiology

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Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end‐stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto‐occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end‐stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near‐linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep—presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)—beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.

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A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer

Cited by 47 publications

References 80 publications

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

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

Quantitative glycoproteomics reveals cellular substrate selectivity of the ER protein quality control sensors UGGT1 and UGGT2

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

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