Autophagy master regulator TFEB induces clearance of toxic SERPINA1/α-1-antitrypsin polymers

Pastore, Nunzia; Ballabio, Andrea; Brunetti‐Pierri, Nicola

doi:10.4161/auto.24469

Cited by 45 publications

(36 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4B (Kukic et al, 2013)], or through its secretion mediated by lysosomal fusion with the plasma membrane. The latter has recently gained a lot of attention as detoxification mechanism in the lysosomal storage diseases (Fraldi et al, 2010;Medina et al, 2011;Palmieri et al, 2011;Decressac et al, 2013;Pastore et al, 2013). The next set of experiments tested the role of lysosomes in Zn 2+ secretion.…”

Section: Resultsmentioning

confidence: 99%

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Kukic

Kelleher

Kiselyov

2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Kukic

Kelleher

Kiselyov

2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Autophagy can be induced by viral vectors that overexpress the autophagy regulator transcription factor EB (TFEB). This reduced the accumulation of Z α 1 -antitrypsin polymer, apoptosis and fibrosis in the liver of the transgenic mouse that expresses Z α 1 -antitrypsin [79]. These approaches reduce intracellular α 1 -antitrypsin burden and decrease hepatic fibrosis in a mouse model of disease.…”

Section: (I) Increasing the Clearance Of Inclusions By Stimulating Aumentioning

confidence: 98%

Update on alpha-1 antitrypsin deficiency: New therapies

Lomas

Hurst

Gooptu

2016

Journal of Hepatology

View full text Add to dashboard Cite

α 1 -antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α 1 -antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α 1 -antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α 1 -antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α 1 -antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies.The detailed understanding of the pathobiology of α 1 -antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials.We provide an overview of these new therapies for the liver and lung disease associated with α 1 -antitrypsin deficiency.

show abstract

“…We found that URMC-099 had no adverse effect on the body weight of the mice (Supplemental Figure 8B). As TFEB induces autophagy in tissue (26,43,44), we tested whether URMC-099 treatment leads to activation of autophagy in spleen and liver. Real-time quantitative PCR (qPCR) showed an upregulation of Tfeb, Map1lc3b, Necn1, and Sqstm1 levels in the livers of URMC-099-treated mice ( Figure 6A).…”

Section: Urmc-099 Retains Arv Nanoparticles In Autophagosomesmentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

show abstract

Autophagy master regulator TFEB induces clearance of toxic SERPINA1/α-1-antitrypsin polymers

Cited by 45 publications

References 0 publications

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Zinc efflux through lysosomal exocytosis prevents zinc-induced toxicity

Update on alpha-1 antitrypsin deficiency: New therapies

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Contact Info

Product

Resources

About