Limits...
Amino-terminal arginylation as a degradation signal for selective autophagy.

Cha-Molstad H, Kwon YT, Kim BY - BMB Rep (2015)

Bottom Line: We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1).The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival.This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins.

View Article: PubMed Central - PubMed

Affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 28116, Korea.

ABSTRACT
The ubiquitin-proteasome system and the autophagy lysosome system are the two major protein degradation machineries in eukaryotic cells. These two systems coordinate the removal of unwanted intracellular materials, but the mechanism by which they achieve this synchronization is largely unknown. The ubiquitination of substrates serves as a universal degradation signal for both systems. Our study revealed that the amino-terminal Arg, a canonical N-degron in the ubiquitin-proteasome system, also acts as a degradation signal in autophagy. We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1). The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival. This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins.

No MeSH data available.


Stress-induced N-end rule pathway regulation of autophagy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4641230&req=5

Figure 001: Stress-induced N-end rule pathway regulation of autophagy.

Mentions: p62 oligomerization is emerging as an important regulatory step of p62 activity and has been shown to be required for p62 targeting to PAS. In addition, p62 interaction with LC3 is required for the p62 integration into maturing autophagosomes. Our data also indicates that this binding of the amino-terminal Arg of BiP to the ZZ domain of p62 leads to p62 oligomerization and aggregation, which stimulates the delivery of Arg-BiP-misfolded protein aggregates to PAS, and their integration into maturing autophagosomes by enhancing the p62 interaction with LC3. Arg-BiP-misfolded protein aggregates eventually undergo p62 and ATG5-dependent autophagic degradation (Fig. 1). This novel pathway protects cells from proteotoxic stress and promotes cell survival.


Amino-terminal arginylation as a degradation signal for selective autophagy.

Cha-Molstad H, Kwon YT, Kim BY - BMB Rep (2015)

Stress-induced N-end rule pathway regulation of autophagy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4641230&req=5

Figure 001: Stress-induced N-end rule pathway regulation of autophagy.
Mentions: p62 oligomerization is emerging as an important regulatory step of p62 activity and has been shown to be required for p62 targeting to PAS. In addition, p62 interaction with LC3 is required for the p62 integration into maturing autophagosomes. Our data also indicates that this binding of the amino-terminal Arg of BiP to the ZZ domain of p62 leads to p62 oligomerization and aggregation, which stimulates the delivery of Arg-BiP-misfolded protein aggregates to PAS, and their integration into maturing autophagosomes by enhancing the p62 interaction with LC3. Arg-BiP-misfolded protein aggregates eventually undergo p62 and ATG5-dependent autophagic degradation (Fig. 1). This novel pathway protects cells from proteotoxic stress and promotes cell survival.

Bottom Line: We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1).The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival.This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins.

View Article: PubMed Central - PubMed

Affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 28116, Korea.

ABSTRACT
The ubiquitin-proteasome system and the autophagy lysosome system are the two major protein degradation machineries in eukaryotic cells. These two systems coordinate the removal of unwanted intracellular materials, but the mechanism by which they achieve this synchronization is largely unknown. The ubiquitination of substrates serves as a universal degradation signal for both systems. Our study revealed that the amino-terminal Arg, a canonical N-degron in the ubiquitin-proteasome system, also acts as a degradation signal in autophagy. We showed that many ER residents, such as BiP, contain evolutionally conserved arginylation permissive pro-N-degrons, and that certain inducers like dsDNA or proteasome inhibitors cause their translocation into the cytoplasm where they bind misfolded proteins and undergo amino-terminal arginylation by arginyl transferase 1 (ATE1). The amino-terminal Arg of BiP binds p62, which triggers p62 oligomerization and enhances p62-LC3 interaction, thereby stimulating autophagic delivery and degradation of misfolded proteins, promoting cell survival. This study reveals a novel ubiquitin-independent mechanism for the selective autophagy pathway, and provides an insight into how these two major protein degradation pathways communicate in cells to dispose the unwanted proteins.

No MeSH data available.