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Location：Home > ApplicationKO Cells Advance Lysosomal Autophagy Regulation Discovery
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KO cells from Ubigene facilitate the discovery of critical regulatory mechanisms in lysosomal autophagy.
Lysosomes are essential organelles within the cell responsible for degrading and recycling materials. They maintain an acidic internal environment (pH 4.5–5.0) to activate various lysosomal hydrolases. Lysosomal membrane proteins are glycosylated to protect them from damage caused by the acidic environment. Dysregulation of lysosome function is associated with a variety of diseases, including lysosomal storage disorders, neurodegenerative diseases, diabetes, and cancer. Lysosomal autophagy is an important process by which cells eliminate damaged lysosomes. However, the specific regulatory mechanisms of lysosomal autophagy are not yet fully understood.
Recently,Na Yeon Park and colleagues published a research paper titled“Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage”in the journal Nature Communications.The study reveals the key regulatory mechanism by which the TBK1-FBXO3-TMEM192-TAX1BP1 axis activates lysophagy in response to lysosomal damage.Specifically,the study utilized FBXO3 gene knockout HepG2 cells constructed by Ubigene to validate the critical role of FBXO3 in lysophagy.
Figure 1. Schematic diagram of lysophagy mechanism mediated by the TBK1-FBXO3-TMEM192-TAX1BP1 axis
Researchers developed a cell-based imaging screening system using enhanced green fluorescent protein (EGFP)-tagged Galectin-3 (EGFP-Gal3) in HepG2 cells. By co-treating with the lysosomotropic agent LLOMe and screening with a ubiquitin compound library, they identified BC-1215 as the most effective regulator of lysosomal autophagy. This finding provides important clues for subsequent research.
Figure 2. Inhibition of FBXO3 reduces the clearance rate of Gal3 puncta and lysophagic flux in HepG2 cells.
Researchers co-treated HepG2/GFP-Gal3 cells with LLOMe and BC-1215 and found that BC-1215 significantly impeded the clearance of damaged lysosomes, with effects similar to those of the autophagy inhibitor bafilomycin A1 (Baf). Moreover, treatment with BC-1215 alone had no impact on the formation of GFP-Gal3 puncta, indicating its specificity for lysophagy in LLOMe-treated cells.
Figure 3. FBXO3 interacts with TMEM192 and mediates the ubiquitination of TMEM192 in LLOMe-treated HepG2 cells.
By knocking down FBXO3 using siRNA, it was found that the clearance of GFP-Gal3 puncta was significantly reduced, similar to the effect observed with BC-1215 treatment. This indicates that FBXO3 plays a crucial role in lysosomal autophagy. Moreover, the interaction between FBXO3 and the lysosomal membrane protein TMEM192 was significantly enhanced after LLOMe treatment, and FBXO3 mediated the ubiquitination of TMEM192, a process that is particularly important following lysosomal damage.
Figure 4. TMEM192 interacts with SQSTM1 and TAX1BP1, acting as an autophagic adaptor in response to lysosomal damage.
The study found that TBK1 is activated following LLOMe treatment, and its inhibitors MRT67307 and GSK8612 reduced the clearance of GFP-Gal3 puncta. This indicates that the activation of TBK1 is crucial for lysosomal autophagy. Through co-immunoprecipitation experiments, researchers discovered that TBK1 interacts with FBXO3 and enhances this interaction following lysosomal damage. Moreover, TBK1 regulates the activity of FBXO3 through phosphorylation, a process that is particularly important after lysosomal damage.
Figure 5. TBK1 is activated and mediates the phosphorylation of FBXO3 in LLOMe-treated HepG2 cells.
Researchers discovered that TMEM192 is ubiquitinated following LLOMe treatment, a process that is dependent on FBXO3. By mutating the lysine residues of TMEM192, the researchers confirmed the crucial role of these residues in the ubiquitination process. Moreover, ubiquitinated TMEM192 facilitates the recruitment of autophagic adaptor proteins SQSTM1 and TAX1BP1, thereby promoting lysosomal autophagy.
Figure 6. The impact of the TBK1-FBXO3-TMEM192-TAX1BP1 axis on lysophagy induced by LLOMe
Integrating the above findings, researchers proposed the critical role of the TBK1-FBXO3-TMEM192-TAX1BP1 axis in lysosomal autophagy. Activation of TBK1 leads to the phosphorylation of FBXO3, which in turn promotes the ubiquitination of TMEM192 and the recruitment of TAX1BP1, ultimately facilitating the clearance of damaged lysosomes. By using inhibitors and gene knockout models, researchers further confirmed the importance of this axis in lysosomal autophagy.
Figure 7. The correlation between FBXO3 and lysophagy induced by LLOMe in FBXO3 knockout HepG2 cells.
For more KO cells, feel free to inquire!
Reference:
Park, Na Yeon, et al. "Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage." Nature Communications 16.1 (2025): 1109.
KO cells from Ubigene facilitate the discovery of critical regulatory mechanisms in lysosomal autophagy.
Lysosomes are essential organelles within the cell responsible for degrading and recycling materials. They maintain an acidic internal environment (pH 4.5–5.0) to activate various lysosomal hydrolases. Lysosomal membrane proteins are glycosylated to protect them from damage caused by the acidic environment. Dysregulation of lysosome function is associated with a variety of diseases, including lysosomal storage disorders, neurodegenerative diseases, diabetes, and cancer. Lysosomal autophagy is an important process by which cells eliminate damaged lysosomes. However, the specific regulatory mechanisms of lysosomal autophagy are not yet fully understood.
Recently,Na Yeon Park and colleagues published a research paper titled“Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage”in the journal Nature Communications.The study reveals the key regulatory mechanism by which the TBK1-FBXO3-TMEM192-TAX1BP1 axis activates lysophagy in response to lysosomal damage.Specifically,the study utilized FBXO3 gene knockout HepG2 cells constructed by Ubigene to validate the critical role of FBXO3 in lysophagy.
Figure 1. Schematic diagram of lysophagy mechanism mediated by the TBK1-FBXO3-TMEM192-TAX1BP1 axis
Researchers developed a cell-based imaging screening system using enhanced green fluorescent protein (EGFP)-tagged Galectin-3 (EGFP-Gal3) in HepG2 cells. By co-treating with the lysosomotropic agent LLOMe and screening with a ubiquitin compound library, they identified BC-1215 as the most effective regulator of lysosomal autophagy. This finding provides important clues for subsequent research.
Figure 2. Inhibition of FBXO3 reduces the clearance rate of Gal3 puncta and lysophagic flux in HepG2 cells.
Researchers co-treated HepG2/GFP-Gal3 cells with LLOMe and BC-1215 and found that BC-1215 significantly impeded the clearance of damaged lysosomes, with effects similar to those of the autophagy inhibitor bafilomycin A1 (Baf). Moreover, treatment with BC-1215 alone had no impact on the formation of GFP-Gal3 puncta, indicating its specificity for lysophagy in LLOMe-treated cells.
Figure 3. FBXO3 interacts with TMEM192 and mediates the ubiquitination of TMEM192 in LLOMe-treated HepG2 cells.
By knocking down FBXO3 using siRNA, it was found that the clearance of GFP-Gal3 puncta was significantly reduced, similar to the effect observed with BC-1215 treatment. This indicates that FBXO3 plays a crucial role in lysosomal autophagy. Moreover, the interaction between FBXO3 and the lysosomal membrane protein TMEM192 was significantly enhanced after LLOMe treatment, and FBXO3 mediated the ubiquitination of TMEM192, a process that is particularly important following lysosomal damage.
Figure 4. TMEM192 interacts with SQSTM1 and TAX1BP1, acting as an autophagic adaptor in response to lysosomal damage.
The study found that TBK1 is activated following LLOMe treatment, and its inhibitors MRT67307 and GSK8612 reduced the clearance of GFP-Gal3 puncta. This indicates that the activation of TBK1 is crucial for lysosomal autophagy. Through co-immunoprecipitation experiments, researchers discovered that TBK1 interacts with FBXO3 and enhances this interaction following lysosomal damage. Moreover, TBK1 regulates the activity of FBXO3 through phosphorylation, a process that is particularly important after lysosomal damage.
Figure 5. TBK1 is activated and mediates the phosphorylation of FBXO3 in LLOMe-treated HepG2 cells.
Researchers discovered that TMEM192 is ubiquitinated following LLOMe treatment, a process that is dependent on FBXO3. By mutating the lysine residues of TMEM192, the researchers confirmed the crucial role of these residues in the ubiquitination process. Moreover, ubiquitinated TMEM192 facilitates the recruitment of autophagic adaptor proteins SQSTM1 and TAX1BP1, thereby promoting lysosomal autophagy.
Figure 6. The impact of the TBK1-FBXO3-TMEM192-TAX1BP1 axis on lysophagy induced by LLOMe
Integrating the above findings, researchers proposed the critical role of the TBK1-FBXO3-TMEM192-TAX1BP1 axis in lysosomal autophagy. Activation of TBK1 leads to the phosphorylation of FBXO3, which in turn promotes the ubiquitination of TMEM192 and the recruitment of TAX1BP1, ultimately facilitating the clearance of damaged lysosomes. By using inhibitors and gene knockout models, researchers further confirmed the importance of this axis in lysosomal autophagy.
Figure 7. The correlation between FBXO3 and lysophagy induced by LLOMe in FBXO3 knockout HepG2 cells.
For more KO cells, feel free to inquire!
Reference:
Park, Na Yeon, et al. "Activation of lysophagy by a TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis in response to lysosomal damage." Nature Communications 16.1 (2025): 1109.
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