LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization

Tanaka, Tsutomu; Warner, Blake M.; Michael, Drew G.; Nakamura, Hiroyuki; Odani, Toshio; Yin, Hongen; Atsumi, Tatsuya; Noguchi, Masayuki; Chiorini, John A.

doi:10.1080/15548627.2021.1995150

Cited by 35 publications

(44 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…LAMP3 overexpression induces apoptosis 4 , 13 . To determine whether the increased apoptosis in naïve cells is associated with apoptosis in EP producer cells, naïve A253 cells were treated with EPs from culture medium of A253 cells treated with staurosporine (STS), which is a general apoptosis inducer and is reported not to induce LAMP3 mRNA expression 28 .…”

Section: Resultsmentioning

confidence: 99%

LAMP3 transfer via extracellular particles induces apoptosis in Sjögren’s disease

Tanaka

Nakamura

Tran

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to extracellular particles (EPs) derived from LAMP3-overexpressing cells showed increased apoptosis. Proteomics identified LAMP3 as a major component of EPs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing EPs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via EPs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.

show abstract

Section: Resultsmentioning

confidence: 99%

LAMP3 transfer via extracellular particles induces apoptosis in Sjögren’s disease

Tanaka

Nakamura

Tran

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…HSG cells, which were kindly provided by Dr. Indu Ambudkar (National Institute of Dental and Craniofacial Research), were cultured in DMEM (Thermo Fisher Scientific, USA) supplemented with 10% FBS and incubated at 37 °C and 5% CO 2 . Transient transfection of LAMP3-encoding plasmid and establishment of stably LAMP3-overexpressing HSG cells were done, as described previously 5 .…”

Section: Discussionmentioning

confidence: 99%

“…In SjD, which is regarded as an epithelitis, epithelial dysfunction of glands is a prominent feature, which can eventually result in epithelial apoptosis 3 . Recent microarray and confocal immunofluorescence studies have shown that increased epithelial apoptosis in salivary glands of SjD patients compared to healthy glands is associated with increased expression of lysosome-associated membrane protein 3 (LAMP3) [4][5][6] . In addition, we have previously shown that LAMP3 overexpression decreases expression of plasma membrane proteins involved in salivation, such as sodium-potassium-chloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5), in salivary gland epithelial cells 6 .…”

mentioning

confidence: 99%

“…4 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan. 5 These authors contributed equally: Hiroyuki Nakamura and Tsutomu Tanaka * email: jchiorini@dir.nidcr.nih.gov of water across plasma membrane and have many key functions including fluid homeostasis and glandular secretion 10,11 . Among the AQPs, AQP5 is expressed in apical membrane of salivary gland epithelial cells, while AQP1 is an archetypical and unregulated water channel that can be expressed on both the apical and basolateral membranes of various cells 11 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Correction of LAMP3-associated salivary gland hypofunction by aquaporin gene therapy

Nakamura

Tanaka

Zheng

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Sjögren’s disease (SjD) is a chronic autoimmune sialadenitis resulting in salivary gland hypofunction with dry mouth symptom. Previous studies showed that lysosome-associated membrane protein 3 (LAMP3) overexpression is involved in the development of salivary gland hypofunction associated with SjD. However, the molecular mechanisms are still unclear, and no effective treatment exists to reverse gland function in SjD. Analysis on salivary gland samples from SjD patients showed that salivary gland hypofunction was associated with decreased expression of sodium–potassium-chloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5), which are membrane proteins involved in salivation. Further studies revealed that LAMP3 overexpression decreased their expression levels by promoting endolysosomal degradation. Additionally, we found that LAMP3 overexpression enhanced gene transfer by increasing internalization of adeno-associated virus serotype 2 (AAV2) via the promoted endolysosomal pathway. Retrograde cannulation of AAV2 vectors encoding AQP1 gene (AAV2-AQP1) into salivary glands induced glandular AQP1 expression sufficient to restore salivary flow in LAMP3-overexpressing mice. LAMP3 could play a critical role in the development of salivary gland hypofunction in SjD by promoting endolysosomal degradation of NKCC1 and AQP5. But it also could enhance AAV2-mediated gene transfer to restore fluid movement through induction of AQP1 expression. These findings suggested that AAV2-AQP1 gene therapy is useful in reversing salivary gland function in SjD patients.

show abstract

“…Recent studies found autophagy plays a key role in protecting against AKI (9,10). Of interest, the effective dynamic process of membrane biogenesis and fusion plays an important role in inducing autophagy (11,12). However, the inducer of this process in kidney injury still needs to be developed.…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 plays a key role in protecting against acute kidney injury through β-catenin/TFEB pathway

Zhou

Shen

Miao

et al. 2022

Preprint

View full text Add to dashboard Cite

Aim Acute kidney injury (AKI) is becoming a heavy health burden worldwide. There are no effective therapeutic strategies nowadays. Recent studies showed that autophagy and lysosome stabilization could inhibit tubular cell apoptosis, and protect against AKI. Annexin A2 (ANXA2), a calcium-regulated phospholipid-binding protein, was found to be highly involved in autophagy. However, its role in AKI has not been elucidated. Results We found that ANXA2 is highly increased in renal tubular cells in cisplatin-treated mice, and in the urine and kidney samples from AKI patients. Ectopic expression of ANXA2 promoted lysosomal functions and autophagic flux, and protected against tubular cell apoptosis in AKI mice. Transcriptome analysis further identified that ANXA2 was intimately correlated with lysosome biogenesis, autophagy, and β-catenin signaling. Mechanistically, ANXA2 induced β-catenin activation through binding to and inhibiting on GSK3β, which further triggered T cell factor 4 (TCF4)-mediated transcription factor EB (TFEB) signaling pathway. As a result, TFEB activation regulated lysosomal proteostasis and effectively promoted autophagic flux. This greatly protected against renal tubular cell apoptosis and alleviated AKI. Innovation: These findings underline ANXA2 serves as a new therapeutic potential for AKI which lacks effective treatment. Conclusion We demonstrated that ANXA2 plays a key role in retarding AKI, which is associated with its inductive effects on β-catenin/TFEB-induced lysosmal pathway.

show abstract

LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization

Cited by 35 publications

References 100 publications

LAMP3 transfer via extracellular particles induces apoptosis in Sjögren’s disease

LAMP3 transfer via extracellular particles induces apoptosis in Sjögren’s disease

Correction of LAMP3-associated salivary gland hypofunction by aquaporin gene therapy

Annexin A2 plays a key role in protecting against acute kidney injury through β-catenin/TFEB pathway

Contact Info

Product

Resources

About