Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis

Santos, Mariela Nunez; Paushter, Daniel H.; Zhang, Tingting; Wu, Xiaochun; Feng, Tuancheng; Lou, Jiaoying; Du, Huan; Becker, Stephanie M.; Fragoza, Robert; Yu, Haiyuan; Hu, Fenghua

doi:10.1016/j.jbc.2022.102348

Cited by 3 publications

(2 citation statements)

References 42 publications

(55 reference statements)

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“…From this analysis, we find that the Ag-high programs overlap with ontology terms suggestive of increased endosomal-lysosomal function (Figure S3A), and this is most significant for cLECs and fLECs. This includes lysosome factors with broad roles in protein homeostasis (Ctsd 25 , Grn 26 , Lgmn 27 , Prcp 28 ), lipid metabolism (Psap 29 ), and lysosome acidification (Atp6v1a 30 ). In addition, expression of the clathrin adaptor protein Dab2 31 may indicate increased endocytic activity.…”

Section: Resultsmentioning

confidence: 99%

A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells

Sheridan,

Doan,

Lucas

et al. 2024

Preprint

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Antigens from protein subunit vaccination traffic from the tissue to the draining lymph node, either passively via the lymph or carried by dendritic cells at the local injection site. Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens, and archived antigen can be released during subsequent inflammatory stimulus to improve immune responses. Here, we answer questions about how LECs achieve durable antigen archiving and whether there are transcriptional signatures associated with LECs containing high levels of antigen. We used single cell sequencing in dissociated LN tissue to quantify antigen levels in LEC and dendritic cell populations at multiple timepoints after immunization, and used machine learning to define a unique transcriptional program within archiving LECs that can predict LEC archiving capacity in independent data sets. Finally, we validated this modeling, showing we could predict antigen archiving from a transcriptional dataset of CHIKV infected mice and demonstratedin vivothe accuracy of our prediction. Collectively, our findings establish a unique transcriptional program in LECs that promotes antigen archiving that can be translated to other systems.

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Section: Resultsmentioning

confidence: 99%

A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells

Sheridan,

Doan,

Lucas

et al. 2024

Preprint

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“…Zhang et al [ 26 ] reported that both GRN A and B are highly expressed in the kidney. Despite being derived from the same precursor, the varying levels of GRN peptides in different organs may be attributed to differences in PGRN processing and lysosomal degradation [ 27 ]. Rolinson et al [ 25 ] reported transcript expression levels after incubation with individual GRN peptides.…”

Section: Discussionmentioning

confidence: 99%

Progranulin deficiency attenuates tubulointerstitial injury in a mouse unilateral ureteral obstruction model

Adachi,

Murakoshi,

Shibata

et al. 2024

Exp. Anim.

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Progranulin (PGRN) may have two opposing effects-inflammation and antiinflammation-in different diseases. Although previous studies have reported that PGRN is involved in liver fibrosis, its involvement in tubulointerstitial fibrosis remains to be fully elucidated. Herein, we investigated these issues using PGRN-knockout (KO) mice treated with unilateral ureteral obstruction (UUO). Eight-week-old male PGRN-KO and wild-type (WT) mice were euthanized 3 and 7 days following UUO, and their kidneys were harvested for histopathological analysis. The renal expression of PGRN was evaluated by immunohistochemical and/or western blot analyses. The renal mRNA levels of markers related to inflammation (Il1b, Tnf, Il6, Ccl2, and Adgre1) and fibrosis (Tgfb1, Acta2, Fn1, and Col1a2) were evaluated using quantitative PCR. Histological changes such as renal tubular atrophy, urinary casts, and tubulointerstitial fibrosis were significantly improved in UUO-KO mice compared with UUO-WT mice. Quantitative PCR revealed that the mRNA expression levels of all inflammation-and fibrosis-related markers were lower in UUO-KO mice than in UUO-WT mice at 3 and/or 7 days after UUO. Moreover, PGRN and GRN protein levels were higher in the kidneys of UUO-WT mice than in mice that did not undergo UUO. Elevated GRN levels associated with excess PGRN levels may be involved in the occurrence of renal inflammation and fibrosis in UUO mice.

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Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia

Simon¹,

Logan²,

DeVos³

2023

Trends in Cell Biology

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Progranulin-derived granulin E and lysosome membrane protein CD68 interact to reciprocally regulate their protein homeostasis

Cited by 3 publications

References 42 publications

A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells

A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells

Progranulin deficiency attenuates tubulointerstitial injury in a mouse unilateral ureteral obstruction model

Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia

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