| Title: |
SIRT4 positively regulates autophagy via ULK1, but independently of HDAC6 and OPA1. |
| Authors: |
Lehmkuhl, Isabell; Amin, Khawar; Gabriel, Lydia; Hampel, Nils; Iram, Afshin; Hesse, Julia; Wiek, Constanze; Nguyen, Jasmin Thuy Vy; Hanenberg, Helmut; Scheller, Jürgen; Ahmadian, M. Reza; Stork, Björn; Floss, Doreen M.; Piekorz, Roland P. |
| Source: |
FEBS Open Bio; May2026, Vol. 16 Issue 5, p870-884, 15p |
| Subject Terms: |
AUTOPHAGY; CELLULAR signal transduction; SERINE/THREONINE kinases; MITOCHONDRIAL proteins; SIRTUINS; HISTONE deacetylases |
| Abstract: |
The sirtuin SIRT4 has been implicated in the control of autophagy and mitochondrial quality control via mitophagy. However, the role of SIRT4 in regulating autophagy/mitophagy induced by different stressors is unclear. Here, we show that cells expressing SIRT4(H161Y), a catalytically inactive, dominant‐negative mutant of SIRT4, fail to upregulate LC3B‐II. These cells also exhibit a reduced autophagic flux upon treatment with different inducers of mitophagy/autophagy, that is, CoCl2‐triggered pseudohypoxia, CCCP (carbonyl cyanide 3‐chlorophenylhydrazone)/oligomycin‐mediated respiratory chain inhibition, or rapamycin treatment. Interestingly, SIRT4(H161Y) expression upregulated protein levels of HDAC6, which is involved in mitochondrial trafficking and autophagosome‐lysosome fusion, and inhibited the conversion of OPA1‐L to OPA1‐S, which is associated with increased mitochondrial fusion and decreased mitophagy. Both HDAC6 and OPA1 are SIRT4 interactors. However, the pharmacological inhibition of HDAC6 using Tubacin or of OPA1 using MYLS22 did not restore the stress‐induced upregulation of LC3B‐II levels upon autophagy/mitophagy treatment in SIRT4(H161Y)‐expressing cells. Remarkably, inhibition of autophagosome–lysosome fusion and thus disruption of late autophagic flux by BafA1 treatment also failed to restore LC3B‐II levels upon autophagy/mitophagy treatment, suggesting an inhibitory effect of SIRT4(H161Y) on the initiation/early phase of autophagy. Consistent with this, we demonstrate that SIRT4(H161Y) promotes the phosphorylation of ULK1 at S638 and S758 (mTORC1 targets), both of which mediate an important inhibitory regulation of autophagy initiation. Thus, our data suggest a positive regulatory function of SIRT4 in the ULK1‐dependent early regulation/initiation of stress‐induced autophagic flux, presumably via modulation of AMPK/mTORC1 signaling. [ABSTRACT FROM AUTHOR] |
| : |
Copyright of FEBS Open Bio is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |