GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Zhang, Weichao; Yang, Xi; Li, Yingxiang; Yu, Linchen; Zhang, Bokai; Zhang, J.; Cho, Woo Jung; Venkatarangan, Varsha; Chen, Liang; Burugula, Bala Bharathi; Bui, Sarah; Wang, Yanzhuang; Duan, Cunming; Kitzman, Jacob O.; Li, Ming

doi:10.1038/s41467-022-33025-1

Cited by 14 publications

(5 citation statements)

References 89 publications

(119 reference statements)

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“…The Lentiviral stable cell lines were generated as described by Zhang, et al ( 57 , 58 ). HEK293T cells were transfected with transfer plasmid, psPAX2 (Addgene 12260), and pMD2.G (Addgene 12259) at 3.5:3.5:1 ratio using Lipofectamine 2000 according to the manufacturer’s instruction.…”

Section: Methodsmentioning

confidence: 99%

ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

Venkatarangan¹,

Zhang²,

Yang³

et al. 2023

Journal of Clinical Investigation

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Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).

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Section: Methodsmentioning

confidence: 99%

ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

Venkatarangan¹,

Zhang²,

Yang³

et al. 2023

Journal of Clinical Investigation

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“…TMEM251, localized in the Golgi apparatus, is indispensable for the cleavage and function of GNPTAB, the enzyme responsible for catalyzing M6P modification. Deletion of TMEM251 results in the mistargeting of most lysosomal enzymes due to the absence of M6P modification, leading to the accumulation of undigested materials ( Zhang et al, 2022 ; Pechincha et al, 2022 ; Richards et al, 2022 ). Furthermore, in zebrafish models, TMEM251 deletion induces severe developmental anomalies reminiscent of Mucolipidosis Type II ( Zhang et al, 2022 ).…”

Section: Interplay Between the Golgi And Lysosomes Under Physiologica...mentioning

confidence: 99%

Golgi defect as a major contributor to lysosomal dysfunction

Akaaboune,

Wang

2024

Front. Cell Dev. Biol.

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The Golgi apparatus plays a crucial role in lysosome biogenesis and the delivery of lysosomal enzymes, essential for maintaining cellular homeostasis and ensuring cell survival. Deficiencies in Golgi structure and function can profoundly impact lysosomal homeostasis, leading to various lysosomal storage diseases and neurodegenerative disorders. In this review, we highlight the role of the Golgi Reassembly Stacking Proteins (GRASPs) in the formation and function of the Golgi apparatus, emphasizing the current understanding of the association between the Golgi apparatus, lysosomes, and lysosomal storage diseases. Additionally, we discuss how Golgi dysfunction leads to the secretion of lysosomal enzymes. This review aims to serve as a concise resource, offering insights into Golgi structure, function, disease-related defects, and their consequential effects on lysosomal biogenesis and function. By highlighting Golgi defects as an underappreciated contributor to lysosomal dysfunction across various diseases, we aim to enhance comprehension of these intricate cellular processes.

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“…Experimental validation via two distinct CRISPR whole-genome knockout-mediated loss-of-function screens confirmed TMEM251’s regulatory role in governing lysosomal biogenesis, prompting its renaming as LYSET. One screen aimed to identify factors associated with deficiencies in lysosomal degradation of RNF152, while the other utilized defects in cathepsin-mediated viral infections (including SARS-CoV-2) as criteria ( Richards et al., 2022 ; Zhang et al., 2022a ).…”

Section: The Components Of the M6p Pathwaymentioning

confidence: 99%

“…Remarkably, in CI-MPR-depleted cells, the secreted hydrolases retained the M6P modification, indicating CI-MPR’s involvement solely in downstream recognition rather than upstream modification. Conversely, hydrolases secreted by cells with GNPT, LYSET single-knockout, and LYSET CI-MPR double-knockout lacked the M6P modification, indicating LYSET’s role in the early stages of the M6P pathway ( Zhang et al., 2022a ). At a molecular level, LYSET assumes a crucial role in coordinating the M6P pathway by reinforcing GNPTAB.…”

Section: The Components Of the M6p Pathwaymentioning

confidence: 99%

The host mannose-6-phosphate pathway and viral infection

Liu,

Wang,

et al. 2024

Front. Cell. Infect. Microbiol.

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Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Cited by 14 publications

References 89 publications

ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine

Golgi defect as a major contributor to lysosomal dysfunction

The host mannose-6-phosphate pathway and viral infection

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