LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles

Qiao, Li; Hu, Jinglu; Qiu, Xueliang; Wang, Chunlin; Peng, Jieqiong; Zhang, Cheng; Zhang, Meng; Lu, Huixia; Chen, Wenqiang

doi:10.1080/15548627.2023.2235196

Cited by 37 publications

(19 citation statements)

References 127 publications

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“…The structural distinctions between LAMP2 isoforms are localized to their C-terminal transmembrane region and cytoplasmic tail. The cytoplasmic tail's positively charged residues are vital for substrate recognition in CMA [39]. Our research demonstrates that alterations to the cytoplasmic tail, either through deletion or modification of these key amino acids, compromise substrate binding and consequently hinder degradation (Figure 2G, H).…”

Section: Discussionmentioning

confidence: 75%

“…Our first piece of evidence supporting the involvement of CMA in the regulation of ATZ comes from the finding that LAMP2A directly interacts with ATZ and promotes its degradation (Figure 1 and 2). LAMP2A, produced by alternative splicing of the LAMP2 gene, is the only isoform implicated in CMA [38,39]. The selective silencing of LAMP2A leads to increased ATZ levels, underscoring CMA's unique role in managing ATZ (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Chaperone-mediated autophagy is an overlooked pathway for mutant α1-antitrypsin Z degradation

Lin,

Lu,

Wei

et al. 2023

Preprint

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Chaperone-mediated autophagy (CMA) is a specific form of autophagy that selectively targets proteins containing a KFERQ-like motif and relies on the chaperone protein HSC70 for substrate recognition. In α1-antitrypsin deficiency (AATD), a disease characterized by the hepatic build-up of α1-Antitrypsin Z mutant (ATZ), CMA’s role had been unclear. This work demonstrates the critical role that CMA plays in preventing ATZ accumulation; suppressing CMA worsens ATZ accumulation, whilst activating it through chemical stimulation or LAMP2A overexpression promotes ATZ breakdown. Specifically, ATZ’s 121QELLR125 motif is critical for HSC70 recognition and LAMP2A’s charged C-terminal cytoplasmic tail is vital for substrate binding, facilitating CMA-mediated degradation of ATZ. This selective activation of CMA operates independently from other autophagy pathways and alleviate ATZ aggregates caused cellular stress. These findings highlight CMA’s critical function in cellular protein quality control of ATZ and place it as a novel target for AATD treatment approaches.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Chaperone-mediated autophagy is an overlooked pathway for mutant α1-antitrypsin Z degradation

Lin,

Lu,

Wei

et al. 2023

Preprint

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“…LAMP2 is a lysosomal-associated membrane protein and constitutes a significant portion of the lysosomal membrane. 48 Lysosomes serve as the main catabolic units responsible for breaking down intracellular proteins via the process of autophagy. 49 The existence of α-synuclein aggregates in PD is potentially mediated by compromised degradation capabilities of lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid using mass spectrometry-based proteomics

Jang,

Oh,

Hall

et al. 2023

Preprint

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Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is often misdiagnosed as Parkinson’s Disease (PD) because of shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, which results in loss of balance, gaze impairment, and dementia. Diagnosing PSP is often challenging, and there’s a significant demand for reliable biomarkers. However, existing biomarkers, including tau protein and neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF), show inconsistencies in distinguishing PSP from other neurodegenerative disorders. To overcome these limitations, we conducted a comprehensive proteome analysis for CSF samples from 40 PSP, 40 PD, and healthy controls (HC) using the tandem mass tag-based quantification method, identifying 3,653 unique proteins. Our statistical analysis identified 190, 152, and 247 differentially expressed proteins when comparing PSP vs. HC, PSP vs. PD, and PSP against both PD and HC, respectively. Gene set enrichment analysis and interactome analysis conducted with the differentially expressed proteins in PSP CSF indicated that most of them were implicated in cell adhesion, cholesterol metabolism, and glycan biosynthesis. Cell-type enrichment analysis revealed that neuronally-derived proteins were predominant among the differentially expressed proteins. Potential biomarker classification performance showed that ATP6AP2 (reduced in PSP) had the highest AUC (0.922), followed by NEFM, EFEMP2, LAMP2, CHST12, FAT2, B4GALT1, LCAT, CBLN3, FSTL5, ATP6AP1, and GGH. This is the first large-scale mass spectrometry-based proteome analysis to discover CSF PSP biomarkers differentiating from both controls and PD, thereby laying a foundation for further development and validation.

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“…Several peptides having cellular specificity can be targeted by selecting through phage display and adhered to the N‐terminal end of Lamp2B in the extracellular membrane of exosomes. [ 113 ] In a study, tLyp‐1‐Lamp2b plasmid‐transfected HEK293T cells releasing tLyp‐1 EEx, which was further encapsulated with siRNA was successfully targeted to reduce the stemness of lung cancer stem cells. [ 114 ] In a similar study involving HER2‐positive breast cancer cells, a lentiviral vector bearing‐Lamp2b‐DARPin G3 chimeric gene was transduced in HEK293T cells, releasing exosomes that had DARPin G3 on their surface.…”

Section: Surface Modification Of the Nex For Cancer Therapymentioning

confidence: 99%

“…Lamp2B complete structure is not known yet, but studies have shown that the N‐terminus of Lamp2B lies outside the exosomal surface membrane that can be affixed with target sequences. [ 113 ] Human Lamp‐2B consists of a larger exterior N‐terminus domain, a shorter C‐terminal region in the transmembrane, and a short cytoplasmic tail. Several peptides having cellular specificity can be targeted by selecting through phage display and adhered to the N‐terminal end of Lamp2B in the extracellular membrane of exosomes.…”

Section: Surface Modification Of the Nex For Cancer Therapymentioning

confidence: 99%

Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics

Sahoo,

Tripathi,

Biswal

et al. 2024

Biotechnology Journal

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Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano‐bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.

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LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles

Cited by 37 publications

References 127 publications

Chaperone-mediated autophagy is an overlooked pathway for mutant α1-antitrypsin Z degradation

Chaperone-mediated autophagy is an overlooked pathway for mutant α1-antitrypsin Z degradation

Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid using mass spectrometry-based proteomics

Transforming native exosomes to engineered drug vehicles: A smart solution to modern cancer theranostics

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