Abstract
Eukaryotic cells are equipped with an efficient quality control system to selectively eliminate misfolded and damaged proteins, and organelles. Abnormal polypeptides that escape from proteasome-dependent degradation and aggregate in the cytosol can be transported via microtubules to inclusion bodies called ‘aggresomes’, where misfolded proteins are confined and degraded by autophagy. Here, we show that Type 2 transglutaminase (TG2) knockout mice display impaired autophagy and accumulate ubiquitinated protein aggregates upon starvation. Furthermore, p62-dependent peroxisome degradation is also impaired in the absence of TG2. We also demonstrate that, under cellular stressful conditions, TG2 physically interacts with p62 and they are localized in cytosolic protein aggregates, which are then recruited into autophagosomes, where TG2 is degraded. Interestingly, the enzyme's crosslinking activity is activated during autophagy and its inhibition leads to the accumulation of ubiquitinated proteins. Taken together, these data indicate that the TG2 transamidating activity has an important role in the assembly of protein aggregates, as well as in the clearance of damaged organelles by macroautophagy.
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Abbreviations
- TG2:
-
Type 2 transglutaminase
- Starv:
-
starvation
- CQ:
-
chloroquine
- 2- DG:
-
2-deoxy-D-glucose
- Rap:
-
rapamycin
- MG132:
-
Z-Leu-Leu-Leu-al
- VCP:
-
valosin-containing protein
- PMP70:
-
peroxisomal membrane protein
- HD:
-
Huntington's disease
- MEFs:
-
mouse embryonic fibroblast
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Acknowledgements
The authors would like to thank Dr. P Mattioli from the Centre of Avanced Microscopy (CAM), Department of Biology, University of Rome Tor Vergata, for her skillful assistance in the use of the facility. This work was supported by grants from CHDI Foundation Inc. (USA), Compagnia di San Paolo, the Ministry of Health of Italy ‘Ricerca Corrente’ and ‘Ricerca Finalizzata’, and AIRC. The support of the EU grant ‘Apo-Sys’ and ‘Transpath’ Marie Curie project to MP is also acknowledged. FC is supported by grants from AIRC, Telethon and FISM.
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D'Eletto, M., Farrace, M., Rossin, F. et al. Type 2 transglutaminase is involved in the autophagy-dependent clearance of ubiquitinated proteins. Cell Death Differ 19, 1228–1238 (2012). https://doi.org/10.1038/cdd.2012.2
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DOI: https://doi.org/10.1038/cdd.2012.2
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