Manganese-induced trafficking and turnover of GPP130 is mediated by sortilin

Venkat, Swati; Linstedt, Adam D.

doi:10.1091/mbc.e17-05-0326

Cited by 16 publications

(11 citation statements)

References 46 publications

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“…This hypothesis is supported by the presence of sortilin in SPG15 pulldowns and its reduction in vesicle-enriched preparations from AP-5 knockout cells. In addition, while this manuscript was in preparation, Vencat and Linstedt reported that the Mn 2+ -induced exit of GOLIM4 from the Golgi is dependent on sortilin, and they suggested that the lumenal domains of the 2 proteins interact with each other [ 38 ]. However, the additive effects of sortilin knockdown and AP-5 knockout indicate that AP-5 can also act in a sortilin-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

et al. 2018

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The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5–associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

et al. 2018

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“…We recently demonstrated that following high Mn 2+ exposure, TMEM165 was targeted to lysosomes for its degradation [15]. The targeting molecular mechanism is unclear but recent investigations propose the requirement of Sortilin in the Mn 2+ induced degradation of TMEM165 [16]. The Mn 2+ sensitivity of the mutated forms of TMEM165 was evaluated.…”

Section: Discussionmentioning

confidence: 99%

Dissection of TMEM165 function in Golgi glycosylation and its Mn2+ sensitivity

et al. 2019

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Since 2012, the interest for TMEM165 increased due to its implication in a rare genetic human disease named TMEM165-CDG (Congenital Disorder(s) of Glycosylation). TMEM165 is a Golgi localized protein, highly conserved through evolution and belonging to the uncharacterized protein family 0016 (UPF0016). Although the precise function of TMEM165 in glycosylation is still controversial, our results highly suggest that TMEM165 would act as a Golgi Ca2+/Mn2+ transporter regulating both Ca2+ and Mn2+ Golgi homeostasis, the latter is required as a major cofactor of many Golgi glycosylation enzymes. Strikingly, we recently demonstrated that besides its role in regulating Golgi Mn2+ homeostasis and consequently Golgi glycosylation, TMEM165 is sensitive to high manganese exposure. Members of the UPF0016 family contain two particularly highly conserved consensus motifs E-φ-G-D-[KR]-[TS] predicted to be involved in the ion transport function of UPF0016 members. We investigate the contribution of these two specific motifs in the function of TMEM165 in Golgi glycosylation and in its Mn2+ sensitivity. Our results show the crucial importance of these two conserved motifs and underline the contribution of some specific amino acids in both Golgi glycosylation and Mn2+ sensitivity.

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“…Sortilin is a Vps10 orthologue that resides primarily in the Golgi and plasma membrane and mediates lysosomal cargo sorting (Nielsen et al, 1999(Nielsen et al, , 2001Lefrancois et al, 2003;Amengual et al, 2018). Similar to its yeast counterpart, sortilin also regulates the lysosomal sorting of misfolded proteins, such as aggregated GPP130, which is induced by manganese (Tewari et al, 2015;Venkat and Linstedt, 2017). Interestingly, while oligomerization/aggregation is sufficient to trigger lysosomal degradation, trafficking is sortilin independent, suggesting that protein aggregation is necessary, but not sufficient, for sortilin-mediated sorting.…”

Section: Receptor-mediated Gqcmentioning

confidence: 99%

Protein quality control in the secretory pathway

Sun

Brodsky

2019

Journal of Cell Biology

302

293

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Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.

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Manganese-induced trafficking and turnover of GPP130 is mediated by sortilin

Abstract: By binding and directing the cycling Golgi protein GPP130 to lysosomes, the sorting receptor sortilin mediates the manganese-induced GPP130 down-regulation that protects against Shiga toxicosis.

Cited by 16 publications

References 46 publications

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval

Dissection of TMEM165 function in Golgi glycosylation and its Mn2+ sensitivity

Protein quality control in the secretory pathway

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