BLOC1S1/GCN5L1/BORCS1 is a critical mediator for the initiation of autolysosomal tubulation

Wu, Kaiyuan; Seylani, Allen; Wu, Jing; Wu, Xufeng; Bleck, Christopher K. E.; Sack, Michael N.

doi:10.1080/15548627.2021.1894759

Cited by 28 publications

(28 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that GCN5L1 possesses distinct functions in mitochondria and lysosomes, 25 we next determined whether mitochondrial‐restricted GCN5L1 (MtG) overexpression sufficed to inhibit liver tumour development. Since 80% of HCCs develop in fibrotic livers due to chronic liver injury, we introduced a mouse model combining DEN and CCl 4 , which promotes liver fibrosis.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma

Zhang

Cui

et al. 2022

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Background Glutaminolysis is a critical metabolic process that promotes cancer cell proliferation, including hepatocellular carcinoma (HCC). Delineating the molecular control of glutaminolysis could identify novel targets to ameliorate this oncogenic metabolic pathway. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a regulator of mitochondrial protein acetylation, in modulating the acetylation and activity of glutaminase to regulate HCC development. Methods Cell proliferation was determined by MTT, 2D and soft agar clone formation assays and orthotopic tumour assays in nude mice. GLS1/2 acetylation and activities were measured in cells and tumours to analyse the correlation with GCN5L1 expression and mTORC1 activation. Results Hepatic GCN5L1 ablation in mice markedly increased diethylnitrosamine (DEN)‐induced HCC, and conversely, the transduction of mitochondrial‐restricted GCN5L1 protected wild‐type mice against HCC progression in response to DEN and carbon tetrachloride (CCl 4 ) exposure. GCN5L1–depleted HepG2 hepatocytes enhanced tumour growth in athymic nude mice. Mechanistically, GCN5L1 depletion promoted cell proliferation through mTORC1 activation. Interestingly, liver–enriched glutaminase 2 (GLS2) appears to play a greater role than ubiquitous and canonical tumour–enriched glutaminase 1 (GLS1) in promoting murine HCC. Concurrently, GCN5L1 promotes acetylation and inactivation of both isoforms and increases enzyme oligomerisation. In human HCC tumours compared to adjacent tissue, there were variable levels of mTORC1 activation, GCN5L1 levels and glutaminase activity. Interestingly, the levels of GCN5L1 inversely correlated with mTORC1 activity and glutaminase activity in these tumours. Conclusions Our study identified that glutaminase activity, rather than GLS1 or GLS2 expression, is the key factor in HCC development that activates mTORC1 and promotes HCC. In the Kaplan–Meier analysis of liver cancer, we found that HCC patients with high GCN5L1 expression survived longer than those with low GCN5L1 expression. Collectively, GCN5L1 functions as a tumour regulator by modulating glutaminase acetylation and activity in the development of HCC.

show abstract

Section: Resultsmentioning

confidence: 99%

Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma

Zhang

Cui

et al. 2022

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hepatocytes from Bloc1s1 liver-specific knockout ( DelVecchio et al, 2002 ) cells accumulate autolysosomes and lysosomes. In LKO hepatocytes, the initiation or extension of lysosomal tubules is abolished, which impairs autophagic lysosome reformation and results in the accumulation of enlarged autolysosomes ( Wu et al, 2021b ). Bloc1s1 degradation by the RIDD pathway promotes BCV perinuclear or ER-region clustering and may also avoid the peripheral movement of BCVs away from the ER region as a consequence of reduced α-tubulin acetylation.…”

Section: Discussionmentioning

confidence: 99%

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Wells

Pandey

et al. 2022

eLife

View full text Add to dashboard Cite

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α-dependent decay (RIDD) of Bloc1s1 mRNA encoding BLOS1, a protein that promotes endosome–lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Inactivation of the Bloc1s1 gene impaired the ability to assemble BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Bloc1s1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus murine hepatitis virus also subverted the RIDD–BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

show abstract

“…It is known that autophagy oc-curs in response to various environmental stresses such as nutrient deficiency, growth factor deficiency, and hypoxia [38]. Many studies have shown that a number of signal transduction pathways are involved in the regulation of autophagy [120,121]. Some autophagic pathways converge at the mTORC1, which plays a central role in the regulation of autophagy [122][123][124][125].…”

Section: Discussionmentioning

confidence: 99%

Effect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP–FRB Interaction and Autophagy

Parada

Oliveira

Gewehr

et al. 2022

Cells

View full text Add to dashboard Cite

Intracellular peptides (InPeps) generated by proteasomes were previously suggested as putative natural regulators of protein–protein interactions (PPI). Here, the main aim was to investigate the intracellular effects of intracellular peptide VFDVELL (VFD7) and related peptides on PPI. The internalization of the peptides was achieved using a C-terminus covalently bound cell-penetrating peptide (cpp; YGRKKRRQRRR). The possible inhibition of PPI was investigated using a NanoBiT® luciferase structural complementation reporter system, with a pair of plasmids vectors each encoding, simultaneously, either FK506-binding protein (FKBP) or FKBP-binding domain (FRB) of mechanistic target of rapamycin complex 1 (mTORC1). The interaction of FKBP–FRB within cells occurs under rapamycin induction. Results shown that rapamycin-induced interaction between FKBP–FRB within human embryonic kidney 293 (HEK293) cells was inhibited by VFD7-cpp (10–500 nM) and FDVELLYGRKKRRQRRR (VFD6-cpp; 1–500 nM); additional VFD7-cpp derivatives were either less or not effective in inhibiting FKBP–FRB interaction induced by rapamycin. Molecular dynamics simulations suggested that selected peptides, such as VFD7-cpp, VFD6-cpp, VFAVELLYGRKKKRRQRRR (VFA7-cpp), and VFEVELLYGRKKKRRQRRR (VFA7-cpp), bind to FKBP and to FRB protein surfaces. However, only VFD7-cpp and VFD6-cpp induced changes on FKBP structure, which could help with understanding their mechanism of PPI inhibition. InPeps extracted from HEK293 cells were found mainly associated with macromolecular components (i.e., proteins and/or nucleic acids), contributing to understanding InPeps’ intracellular proteolytic stability and mechanism of action-inhibiting PPI within cells. In a model of cell death induced by hypoxia-reoxygenation, VFD6-cpp (1 µM) increased the viability of mouse embryonic fibroblasts cells (MEF) expressing mTORC1-regulated autophagy-related gene 5 (Atg5), but not in autophagy-deficient MEF cells lacking the expression of Atg5. These data suggest that VFD6-cpp could have therapeutic applications reducing undesired side effects of rapamycin long-term treatments. In summary, the present report provides further evidence that InPeps have biological significance and could be valuable tools for the rational design of therapeutic molecules targeting intracellular PPI.

show abstract

BLOC1S1/GCN5L1/BORCS1 is a critical mediator for the initiation of autolysosomal tubulation

Cited by 28 publications

References 48 publications

Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma

Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma

Brucella activates the host RIDD pathway to subvert BLOS1-directed immune defense

Effect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP–FRB Interaction and Autophagy

Contact Info

Product

Resources

About