2022
DOI: 10.1038/s41467-022-33025-1
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GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway

Abstract: The mannose-6-phosphate (M6P) biosynthetic pathway for lysosome biogenesis has been studied for decades and is considered a well-understood topic. However, whether this pathway is regulated remains an open question. In a genome-wide CRISPR/Cas9 knockout screen, we discover TMEM251 as the first regulator of the M6P modification. Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. We further demonstrate that TMEM2… Show more

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Cited by 14 publications
(5 citation 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%
“…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%
“…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%
“…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%