Faculty Opinions recommendation of Lysosomal proteases are involved in generation of N-terminal huntingtin fragments.

2006 ◽  
Author(s):  
Allan Tobin
Keyword(s):  
Lysosomal Proteases

scholarly journals Relationship between Degradation Rates of Proteins in Vivo and Their Susceptibility to Lysosomal Proteases

1974 ◽  
Vol 249 (19) ◽  
pp. 6364-6365
Author(s):  
Harold I. Segal ◽  
James R. Winkler ◽  
Mary P. Miyagi
Keyword(s):  
Degradation Rates ◽  
Lysosomal Proteases

Fibroblast Growth Factor 23 (FGF23) leads to endolysosomal routing of the renal phosphate co-transporters NaPi-IIa and NaPi-IIc in vivo

2021 ◽  
Author(s):  
Catharina J Küng ◽  
Betül Haykir ◽  
Udo Schnitzbauer ◽  
Daniela Egli-Spichtig ◽  
Nati Hernando ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Time Course ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Extracellular Signal ◽  
Early Endosomes ◽  
Lysosomal Proteases ◽  
Intracellular Pathway

The sodium-dependent phosphate co-transporters NaPi-IIa and NaPi-IIc located at the brush border membrane of renal proximal tubules are regulated by numerous factors, including fibroblast growth factor 23 (FGF23). FGF23 downregulates NaPi-IIa and NaPi-IIc abundance after activating a signaling pathway involving phosphorylation of the extracellular signal-regulated protein kinase (phospho-ERK1/2). FGF23 also downregulates the expression of renal 1-α-hydroxylase (Cyp27b1) and upregulates 24-hydroxylase (Cyp24a1), thus reducing plasma calcitriol levels. Here, we examined the time course of the FGF23-induced internalization of NaPi-IIa and NaPi-IIc and their intracellular pathway towards degradation in vivo. Mice were injected intraperitoneally with recombinant human FGF23 (rh-FGF23) in the absence (biochemical analysis) or presence (immunohistochemistry) of leupeptin, an inhibitor of lysosomal proteases. Phosphorylation of ERK1/2 was enhanced 60 minutes after rh-FGF23 administration, and increased phosphorylation was still detected 480 minutes post-injection. Co-localization of phospho-ERK1/2 with NaPi-IIa was seen at 60, 120 and partly at 480 minutes. The abundance of both co-transporters was reduced 240 minutes after rh-FGF23 administration, with a further reduction at 480 minutes. NaPi-IIa and NaPi-IIc were found to co-localize with clathrin and early endosomal antigen 1 (EEA1) as early as 120 minutes after rh-FGF23 injection. Both co-transporters partially co-localized with cathepsin B and Lamp1, markers of lysosomes, 120 minutes after rh-FGF23 injection. Thus, NaPi-IIa and NaPi-IIc are internalized within 2 hours upon rh-FGF23 injection. Both co-transporters share the pathway of clathrin-mediated endocytosis that leads first to early endosomes, finally resulting in trafficking towards the lysosome as early as 120 minutes after rh-FGF23 administration.

Inhibition of the Acid Lipase Activity by Apolipoprotein A-I in the Presence of Lysosomal Proteases

1999 ◽  
Vol 63 (5) ◽  
pp. 937-939
Author(s):  
Yuichi INOUE ◽  
Takeshi OSE ◽  
Satoru MUKAI ◽  
Shunji EHIRA ◽  
Masami YONEKURA ◽  
...  
Keyword(s):  
Lipase Activity ◽  
Acid Lipase ◽  
Apolipoprotein A ◽  
Lysosomal Proteases

Dietary protein deficiency reduces lysosomal and nonlysosomal ATP-dependent proteolysis in muscle

1992 ◽  
Vol 263 (2) ◽  
pp. E326-E334 ◽  
Author(s):  
N. E. Tawa ◽  
I. C. Kettelhut ◽  
A. L. Goldberg
Keyword(s):  
Skeletal Muscle ◽  
Dietary Protein ◽  
Cathepsin B ◽  
Normal Diet ◽  
Optimal Conditions ◽  
Protein Breakdown ◽  
Lysosomal Hydrolases ◽  
Lysosomal Protease ◽  
Lysosomal Proteases ◽  
Dependent Processes

When rats are fed a protein deficient (PD) diet for 7 days, rates of proteolysis in skeletal muscle decrease by 40-50% (N. E. Tawa, Jr., and A. L. Goldberg. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E317-325, 1992). To identify the underlying biochemical adaptations, we measured different proteolytic processes in incubated muscles. The capacity for intralysosomal proteolysis, as shown by sensitivity to methylamine or lysosomal protease inhibitors, fell 55-75% in muscles from PD rats. Furthermore, extracts of muscles of PD rats showed 30-70% lower activity of many lysosomal proteases, including cathepsins B, H, and C, and carboxypeptidases A and C, as well as other lysosomal hydrolases. The fall in cathepsin B and proteolysis was evident by 3 days on the PD diet, and both returned to control levels 3 days after refeeding of the normal diet. In muscles maintained under optimal conditions, 80-90% of protein breakdown occurs by nonlysosomal pathways. In muscles of PD rats, this ATP-dependent process was also 40-60% slower. Even though overall proteolysis decreased in muscles of PD rats, their capacity for Ca(2+)-dependent proteolysis increased (by 66%), as did the activity of the calpains (+150-250%). Thus the lysosomal and the ATP-dependent processes decrease coordinately and contribute to the fall in muscle proteolysis in PD animals.

scholarly journals A Forward Genetic Strategy Reveals Destabilizing Mutations in the Ebolavirus Glycoprotein That Alter Its Protease Dependence during Cell Entry

2009 ◽  
Vol 84 (1) ◽  
pp. 163-175 ◽  
Author(s):  
Anthony C. Wong ◽  
Rohini G. Sandesara ◽  
Nirupama Mulherkar ◽  
Sean P. Whelan ◽  
Kartik Chandran
Keyword(s):  
Proteolytic Processing ◽  
Cell Entry ◽  
Cleavage Sites ◽  
Viral Glycoprotein ◽  
Enveloped Virus ◽  
Cysteine Cathepsins ◽  
Vesicular Stomatitis ◽  
Lysosomal Proteases ◽  
Conformational Rearrangements ◽  
Viral Membrane Fusion

ABSTRACT Ebolavirus (EBOV) entry into cells requires proteolytic disassembly of the viral glycoprotein, GP. This proteolytic processing, unusually extensive for an enveloped virus entry protein, is mediated by cysteine cathepsins, a family of endosomal/lysosomal proteases. Previous work has shown that cleavage of GP by cathepsin B (CatB) is specifically required to generate a critical entry intermediate. The functions of this intermediate are not well understood. We used a forward genetic strategy to investigate this CatB-dependent step. Specifically, we generated a replication-competent recombinant vesicular stomatitis virus bearing EBOV GP as its sole entry glycoprotein and used it to select viral mutants resistant to a CatB inhibitor. We obtained mutations at six amino acid positions in GP that independently confer complete resistance. All of the mutations reside at or near the GP1-GP2 intersubunit interface in the membrane-proximal base of the prefusion GP trimer. This region forms a part of the “clamp” that holds the fusion subunit GP2 in its metastable prefusion conformation. Biochemical studies suggest that most of the mutations confer CatB independence not by altering specific cleavage sites in GP but rather by inducing conformational rearrangements in the prefusion GP trimer that dramatically enhance its susceptibility to proteolysis. The remaining mutants did not show the preceding behavior, indicating the existence of multiple mechanisms for acquiring CatB independence during entry. Altogether, our findings suggest that CatB cleavage is required to facilitate the triggering of viral membrane fusion by destabilizing the prefusion conformation of EBOV GP.

scholarly journals Sphingomyelins suppress the targeted disruption of lysosomes/endosomes by the photosensitizer NPe6 during photodynamic therapy

2005 ◽  
Vol 392 (2) ◽  
pp. 325-334 ◽  
Author(s):  
Joseph A. Caruso ◽  
Patricia A. Mathieu ◽  
John J. Reiners
Keyword(s):  
Rapid Loss ◽  
Targeted Disruption ◽  
Apoptotic Pathway ◽  
Acridine Orange Staining ◽  
Late Endosomes ◽  
Lysosomal Proteases ◽  
Pre Treatment ◽  
Factor Α ◽  
Acidic Organelles ◽  
Necrosis Factor

Recent studies have described a biochemical pathway whereby lysosome disruption and the released proteases initiate the intrinsic apoptotic pathway. Irradiation of murine hepatoma 1c1c7 cells preloaded with the lysosomal photosensitizer NPe6 (N-aspartyl chlorin e6) caused a rapid loss of Acridine Orange staining of acidic organelles, release of cathepsin D from late endosomes/lysosomes and the activation of procaspase-3. Pretreatment of NPe6-loaded cultures with 10–50 μM 3-O-MeSM (3-O-methylsphingomyelin) caused a concentration-dependent suppression of apoptosis following irradiation. This suppression reflected a stabilization of lysosomes/endosomes, as opposed to an inhibition of the accumulation of photosensitizer in these organelles. Exogenously added sphingomyelin, at comparable concentrations, offered some protection, but less than 3-O-MeSM. Fluorescence microscopy showed that 3-O-MeSM competed with NBD-C6-sphingomyelin (6-{[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoyl} sphingosyl phosphocholine) for co-localization with LysoTracker Red in acidic organelles. Pre-treatment of 1c1c7 cultures with 3-O-MeSM also suppressed the induction of apoptosis by TNFα (tumour necrosis factor α), but offered no protection against HA14-1 [ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate], staurosporine, tunicamycin or thapsigargin. These results suggest that exogenously added 3-O-MeSM is trafficked to and stabilizes late endosomes/lysosomes against oxidant-induced damage, and further implicate a role for lysosomal proteases in the apoptotic processes initiated by TNFα and lysosomal photosensitizers.

scholarly journals Specific functions of lysosomal proteases in endocytic and autophagic pathways

2012 ◽  
Vol 1824 (1) ◽  
pp. 34-43 ◽  
Author(s):  
Sabrina Müller ◽  
Julia Dennemärker ◽  
Thomas Reinheckel
Keyword(s):  
Lysosomal Proteases
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