CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis

Ronza, Alberto di; Bajaj, Lakshya; Sharma, Jaiprakash; Sanagasetti, Deepthi; Lotfi, Parisa; Adamski, Carolyn J.; Collette, John R.; Palmieri, Michela; Amawi, Abdallah; Popp, Lauren; Chang, K. T.; Meschini, Maria Chiara; Leung, Hon Chiu Eastwood; Segatori, Laura; Simonati, Alessandro; Sifers, Richard N.; Santorelli, Filippo M.; Sardiello, Marco

doi:10.1038/s41556-018-0228-7

Cited by 91 publications

(115 citation statements)

References 38 publications

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“…Immunoblot analysis for the lysosomal membrane protein LAMP1 confirmed lysosomal enrichment in the collected fractions and showed no obvious changes in LAMP1 signal between WT and Cln6 -/samples (Supplemental Figure 1A). We confirmed lysosomal enrichment by performing enzyme assay for β-hexosaminidase, a lysosomal enzyme that is not affected by CLN8 deficiency (4) and that also did not show changes upon deficiency of CLN6 (Supplemental Figure 1B). We then performed immunoblot analysis for a set of enzymes for which antibodies able to recognize the mouse proteins are available.…”

Section: Loss Of Cln6 Does Not Aggravate Pathology Of Cln8-deficient mentioning

confidence: 54%

“…CLN8 is a ubiquitously expressed, multi-pass membrane protein that forms homodimers and localizes in the ER and the ER-Golgi intermediate compartment (5,6). CLN8 interacts with newly synthesized lysosomal enzymes in the ER, transfer them to the Golgi via COPII vesicles, and recycles back to the ER via COPI vesicles (4). Absence of CLN8 results in inefficient ER exit and decreased levels of lysosomal enzymes in mouse tissues and patient-derived cells (4), resulting in a subtype of Batten disease or neuronal ceroid lipofuscinosis (NCL) (7,8).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, at least four other NCL genes encode proteins that localize and presumably function in the lysosome (10). Impaired trafficking of lysosomal enzymes due to CLN8 deficiency is another example linking impaired protein function to NCL molecular pathology (4).…”

Section: Introductionmentioning

confidence: 99%

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

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8. Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system) which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Simultaneous deficiency of CLN6 and CLN8 did not aggravate mouse pathology compared to the single deficiencies, indicating that the EGRESS complex works as a functional unit. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8, and in vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.

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Section: Loss Of Cln6 Does Not Aggravate Pathology Of Cln8-deficient mentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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

Bajaj

Ronza

Zheng³

et al. 2019

Preprint

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“…The formation of mature lysosomes is a complex process, which involves the fusion of late endosomes that contain material taken up at the cell surface with transport ves icles that bud from the trans Golgi network 5,8,17 . These vesicles contain nearly 60 different hydrolytic enzymes (grouped into nucleases, proteases, phosphatases, lipases, and regulation of exogenous and endogenous cellular material, including recycling processes.…”

Section: Lysosomal Biogenesis Structure and Functionmentioning

confidence: 99%

“…Strikingly, however, this field has not been extensively explored. However, elevated levels of lysosomal enzyme activity have been reported to occur in several autoimmune diseases, such as RA, systemic lupus erythematosus (SLE), dermatomyositis and psoriasis 3,14,17,18,[20][21][22][23] .…”

Section: Autoimmune Disordersmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

500

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Batten disease through different in vivo and in vitro models: A review

Nittari

Tomassoni

Roy

et al. 2022

J of Neuroscience Research

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Batten disease consists of a family of primarily autosomal recessive, progressive neuropediatric disorders, also known as neuronal ceroid lipofuscinoses (NCLs). These pathologies are characterized by seizures and visual, cognitive and motor decline, and premature death. The pathophysiology of this rare disease is still unclear despite the years of trials and financial aids. This paper has reviewed advantages and limits of in vivo and in vitro models of Batten disease from murine and larger animal models to primitive unicellular models, until the most recently developed patient‐derived induced pluripotent stem cells. For each model advantages, limits and applications were analyzed. The first prototypes investigated were murine models that due to their limits were replaced by larger animals. In vitro models gradually replaced animal models for practical, cost, and ethical reasons. Using induced pluripotent stem cells to study neurodegeneration is a new way of studying the disease, since they can be distinguished into differentiating elements like neurons, which are susceptible to neurodegeneration. In vivo and in vitro models have contributed to clarifying to some extent the pathophysiology of the disease. The collection and sharing of suitable human bio samples likely through biobanks can contribute to a better understanding, prevention, and to identify possible treatment strategies of Batten disease.

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CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis

Cited by 91 publications

References 38 publications

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

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

Lysosomes as a therapeutic target

Batten disease through different in vivo and in vitro models: A review

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