Different Pathways to the Lysosome

Hasanagic, Medina; Waheed, Abdül; Eissenberg, Joel C.

doi:10.1016/bs.ircmb.2015.07.008

Cited by 14 publications

(13 citation statements)

References 139 publications

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“…Over 50 soluble hydrolases, including cathepsins, have been found in lysosomes . These hydrolases are synthesized in the rough endoplasmic reticulum and travel along the secretory pathway until they reach the TGN, where they are sorted and delivered to late endosomes/lysosomes . The inhibition of lysosomal hydrolases, such as cathepsins, can induce lysosome dysfunction and prevent autophagic degradation .…”

Section: Resultsmentioning

confidence: 99%

Control of Rab7a activity and localization through endosomal type Igamma PIP 5‐kinase is required for endosome maturation and lysosome function

et al. 2019

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The small GTPase Ras‐related protein Rab‐7a (Rab7a) serves as a key organizer of the endosomal‐lysosomal system. However, molecular mechanisms controlling Rab7a activation levels and subcellular translocation are still poorly defined. Here, we demonstrate that type Igamma phosphatidylinositol phosphate 5‐kinase i5 (PIPKIγi5), an endosome‐localized enzyme that produces phosphatidylinositol 4,5‐bisphosphate, directly interacts with Rab7a and plays critical roles in the control of the endosomal‐lysosomal system. The loss of PIPKIγi5 blocks Rab7a recruitment to early endosomes, which prevents the maturation of early to late endosomes. PIPKIγi5 loss disturbs retromer complex connection with Rab7a, which blocks the retrograde sorting of Cation‐independent Mannose 6‐Phosphate Receptor from late endosomes. This leads to the decreased sorting of hydrolases to lysosomes and reduces the autophagic degradation. By modulating the retromer‐Rab7a connection, PIPKIγi5 is also required for the recruitment of the GTPase‐activating protein TBC1 domain family member 5 to late endosomes, which controls the conversion of Rab7a from the active state to the inactive state. Thus, PIPKIγi5 is critical for the modulation of Rab7a activity, localization, and function in the endosomal‐lysosomal system.

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Section: Resultsmentioning

confidence: 99%

Control of Rab7a activity and localization through endosomal type Igamma PIP 5‐kinase is required for endosome maturation and lysosome function

et al. 2019

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“…Direct targeting the FcRn was not possible because commercially available antibodies failed to give specific signals, but the assessed proteins were reported to be crucially involved either in the transport of FcRn/IgG-complexes or in lysosomal processes in endothelial cells (EC) or other cell types [7, 11–17, 31–34]. …”

Section: Resultsmentioning

confidence: 99%

“…Internalized aflibercept might be degraded, and proteins destined for degradation were detected in multivesicular endosomes, characteristically containing CI-M6PR involved in the transport of hydrolases from the trans-Golgi network to lysosomes [17]. Remarkably, the immunofluorescence stainings of aflibercept and CI-M6PR observed in the cells’ perinuclear regions widely overlapped (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…That aflibercept has an Fc terminus suggests involvement of the FcRn in its transport and protection from proteolysis. To further elucidate aflibercept’s fate inside iBREC, we performed double immunofluorescence stainings with marker proteins either associated with an FcRn-mediated transport (→ EEA1, Rab4, Rab11) or with the lysosomal pathway in EC (→ CI-M6PR, Rab7) [13–17, 34]. We also included proteins of the cytoskeleton (→ α-tubulin, actin, vimentin) as well as motor proteins (→ dynein, kinesin) in our analyses because these might play a role in FcRn-mediated transport along microtubules [31–33].…”

Section: Discussionmentioning

confidence: 99%

“…FcRn-bound IgG is then transported by recycling exosomes (positive for Rab11 but not for Rab4) to be released at the cell surface, thereby avoiding subsequent intracellular degradation in lysosomes [13, 15, 16]. In contrast, unbound IgG or other proteins destined to be eventually degraded in lysosomes, could be detected at an earlier stage mainly in multivesicular endosomes characterized by the presence of the cation-independent mannose 6-phosphate receptor (CI-M6PR) [17]. …”

Section: Introductionmentioning

confidence: 99%

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Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation

Deissler

Lang

2018

Graefes Arch Clin Exp Ophthalmol

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PurposeIntravitreal injection of the VEGF-binding protein aflibercept is widely used to treat various ocular diseases. In vitro, immortalized bovine retinal endothelial cells (iBREC) take up and transport aflibercept through the cell layer in a serum-dependent manner, likely mediated through the neonatal Fc receptor (FcRn), but degradation of the Fc domain-containing protein might be a competing intracellular process. Therefore, aflibercept’s associations with proteins either involved in FcRn-mediated transport or in the lysosomal pathway were studied.MethodsConfluent iBREC pre-cultivated with or without FBS were exposed for 4 h to in vivo achievable 250 μg/ml aflibercept, before cells were harvested for immunofluorescence staining or preparation of protein extracts. Intracellular localization of aflibercept and putative co-localizations with proteins involved in transport of IgG/FcRn complexes, i.e., endosomal Rab4 and Rab11, components of the cytoskeleton, motor proteins, or with marker proteins characteristic of multivesicular bodies or lysosomes were assessed by co-immunofluorescence stainings. Amounts of expressed endogenous proteins and of internalized aflibercept were determined by Western blot analyses.ResultsAflibercept-specific perinuclear staining overlapped with that of the motor protein dynein whereas double staining with an anti-kinesin antibody resulted in a patchy pattern. In addition, aflibercept was typically present close to microtubules and often co-localized with α-tubulin. Rab4 and Rab11 stainings partly overlapped with the perinuclear staining of aflibercept whereas co-localization with Rab7 (in late endosomes/lysosomes) was only rarely seen. Interestingly, aflibercept but not the IgG bevacizumab broadly co-localized with the cation-independent mannose 6-phosphate receptor characteristic of multivesicular endosomes. In accordance with partial degradation beside transcytosis, the amount of intracellular aflibercept increased when cells were treated with protease inhibitors MG-132 or MG-101. Serum-deprived iBREC expressed less Rab11 and dynein but slightly more Rab4.ConclusionAfter uptake by iBREC, aflibercept is present in organelles associated with FcRn-mediated transport, but part of the protein is subject to degradation. Transport inhibition of aflibercept during cultivation without FBS is likely a consequence of an attenuated exocytosis due to decreased expression of Rab11.

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Multiple Roles of Rab GTPases at the Golgi

Progida

2019

Results and Problems in Cell Differentiation

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Different Pathways to the Lysosome

Cited by 14 publications

References 139 publications

Control of Rab7a activity and localization through endosomal type Igamma PIP 5‐kinase is required for endosome maturation and lysosome function

Control of Rab7a activity and localization through endosomal type Igamma PIP 5‐kinase is required for endosome maturation and lysosome function

Fate of the Fc fusion protein aflibercept in retinal endothelial cells: competition of recycling and degradation

Multiple Roles of Rab GTPases at the Golgi

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