Elucidating the mechanism by which phosphorylation determines protein degradation efficiency
Juntendo University researchers discovered that the properties of p62 protein aggregates, crucial for cellular "autophagy," are altered by phosphorylation, thereby dictating degradation efficiency. This breakthrough, published in EMBO Journal, reveals how aggregates become more compact and degradable, offering new insights into protein quality control relevant to neurodegenerative diseases.
📋 Article Processing Timeline
- 📰 Published: May 6, 2026 at 03:27
- 🔍 Collected: May 5, 2026 at 18:31
- 🤖 AI Analyzed: May 5, 2026 at 18:33 (1 min after Collected)
## Press Release Information
Title: Elucidating the mechanism by which phosphorylation determines protein degradation efficiency
A research group led by Professor Masaaki Komatsu of the Department of Organ and Cell Physiology, Graduate School of Medicine, Juntendo University, has clarified that in "autophagy*¹," a mechanism for degrading unnecessary proteins in cells, the properties of aggregates formed by the protein p62*² are altered by phosphorylation*³, thereby determining their degradation efficiency. In cells, denatured and dysfunctional proteins are ultimately tagged with "ubiquitin*⁴" and degraded. This study showed that p62 aggregates, which collect denatured, dysfunctional, and ubiquitinated proteins, change into a more compact state due to phosphorylation, acquiring properties suitable for degradation. This finding is expected to contribute to the understanding of protein quality control involved in neurodegenerative diseases. This paper was published online in EMBO Journal on May 5, 2026.
Highlights of this Research Achievement
- Clarified the phosphorylation regulatory mechanism (TBK1 and PP2A) in p62 aggregates.
- Confirmed that phosphorylation changes the aggregates from a "fluid" to a "compact state."
- Demonstrated that the "property" of the aggregates themselves determines the degradation efficiency of unwanted proteins.
Background
In cells, the accumulation of denatured or damaged proteins that have lost their function leads to cellular dysfunction and the onset of diseases. These proteins are tagged with a marker called "ubiquitin" and are degraded by autophagy. p62 plays a crucial role in collecting these ubiquitinated proteins to form aggregates (p62 bodies) and directing them towards degradation. Recently, these aggregates have been understood as structures with liquid-like properties, but it was unclear what state of aggregates would be efficiently degraded. This research focused on the phosphorylation of p62 and aimed to elucidate its role.
Content
In this study, to clarify the phosphorylation control and its function in p62 aggregates, we conducted an integrated analysis combining cultured cell analysis, in vitro reconstitution experiments, microscopic observation, and analysis using genetically modified mice. The results revealed that the phosphorylation enzyme TBK1 and the dephosphorylation enzyme PP2A regulate the phosphorylation state of p62. Furthermore, phosphorylation at a specific site (Ser403) of p62 was found to change the aggregates from a large, fluid state to a small, compact, and stable state. This change was shown to promote interaction with membrane structures involved in autophagy, thereby efficiently promoting the degradation of aggregates. This phenomenon was confirmed not only in cultured cells but also in individual mice. From these results, it was demonstrated that p62 phosphorylation functions as a molecular switch that changes the properties of aggregates, thereby influencing the degradation efficiency of unnecessary proteins.
Future Development
This research demonstrates the possibility that protein degradation efficiency is regulated by the "property" of the aggregates. Until now, autophagy research has focused on the degradation pathway itself, but this achievement provides a new perspective: the control of the physical properties of the degradation targets. It is expected that clarifying the role of this mechanism in pathological conditions characterized by the accumulation of abnormal proteins, such as neurodegenerative diseases and cancer, will lead to the development of new therapeutic strategies.
Figure 1: The "property of protein clumps" determines degradation efficiency
Inside cells, unnecessary or damaged proteins are degraded by a mechanism called "autophagy." At that time, a protein called p62 collects these proteins to form "clumps (aggregates)" and guides them to degradation. This figure shows that the property of these p62 aggregates changes significantly due to a chemical modification called "phosphorylation." When phosphorylation is low, p62 aggregates are "large and fluid (liquid-like)" and are difficult to degrade. On the other hand, when p62 is phosphorylated by an enzyme called TBK1, the p62 aggregates become "small and somewhat solid (gel-like)" and become easier to degrade. This change can also be reversed by an enzyme called PP2A, making it a reversible change. In other words, it was found that p62 aggregates are not just "collections," but their properties (softness and size) determine how easily they are degraded.
Terminology
*1 Autophagy: A mechanism for degrading unnecessary substances and abnormal proteins in cells.
*2 p62: A protein that collects ubiquitinated proteins and guides them to degradation.
*3 Phosphorylation: A chemical modification that changes the function and properties of proteins.
*4 Ubiquitin: A marker molecule attached to proteins that should be degraded.
Researcher's Comment
This achievement involved a highly specialized technical staff member as the lead author, who was central to the meticulous research.
Title: Elucidating the mechanism by which phosphorylation determines protein degradation efficiency
A research group led by Professor Masaaki Komatsu of the Department of Organ and Cell Physiology, Graduate School of Medicine, Juntendo University, has clarified that in "autophagy*¹," a mechanism for degrading unnecessary proteins in cells, the properties of aggregates formed by the protein p62*² are altered by phosphorylation*³, thereby determining their degradation efficiency. In cells, denatured and dysfunctional proteins are ultimately tagged with "ubiquitin*⁴" and degraded. This study showed that p62 aggregates, which collect denatured, dysfunctional, and ubiquitinated proteins, change into a more compact state due to phosphorylation, acquiring properties suitable for degradation. This finding is expected to contribute to the understanding of protein quality control involved in neurodegenerative diseases. This paper was published online in EMBO Journal on May 5, 2026.
Highlights of this Research Achievement
- Clarified the phosphorylation regulatory mechanism (TBK1 and PP2A) in p62 aggregates.
- Confirmed that phosphorylation changes the aggregates from a "fluid" to a "compact state."
- Demonstrated that the "property" of the aggregates themselves determines the degradation efficiency of unwanted proteins.
Background
In cells, the accumulation of denatured or damaged proteins that have lost their function leads to cellular dysfunction and the onset of diseases. These proteins are tagged with a marker called "ubiquitin" and are degraded by autophagy. p62 plays a crucial role in collecting these ubiquitinated proteins to form aggregates (p62 bodies) and directing them towards degradation. Recently, these aggregates have been understood as structures with liquid-like properties, but it was unclear what state of aggregates would be efficiently degraded. This research focused on the phosphorylation of p62 and aimed to elucidate its role.
Content
In this study, to clarify the phosphorylation control and its function in p62 aggregates, we conducted an integrated analysis combining cultured cell analysis, in vitro reconstitution experiments, microscopic observation, and analysis using genetically modified mice. The results revealed that the phosphorylation enzyme TBK1 and the dephosphorylation enzyme PP2A regulate the phosphorylation state of p62. Furthermore, phosphorylation at a specific site (Ser403) of p62 was found to change the aggregates from a large, fluid state to a small, compact, and stable state. This change was shown to promote interaction with membrane structures involved in autophagy, thereby efficiently promoting the degradation of aggregates. This phenomenon was confirmed not only in cultured cells but also in individual mice. From these results, it was demonstrated that p62 phosphorylation functions as a molecular switch that changes the properties of aggregates, thereby influencing the degradation efficiency of unnecessary proteins.
Future Development
This research demonstrates the possibility that protein degradation efficiency is regulated by the "property" of the aggregates. Until now, autophagy research has focused on the degradation pathway itself, but this achievement provides a new perspective: the control of the physical properties of the degradation targets. It is expected that clarifying the role of this mechanism in pathological conditions characterized by the accumulation of abnormal proteins, such as neurodegenerative diseases and cancer, will lead to the development of new therapeutic strategies.
Figure 1: The "property of protein clumps" determines degradation efficiency
Inside cells, unnecessary or damaged proteins are degraded by a mechanism called "autophagy." At that time, a protein called p62 collects these proteins to form "clumps (aggregates)" and guides them to degradation. This figure shows that the property of these p62 aggregates changes significantly due to a chemical modification called "phosphorylation." When phosphorylation is low, p62 aggregates are "large and fluid (liquid-like)" and are difficult to degrade. On the other hand, when p62 is phosphorylated by an enzyme called TBK1, the p62 aggregates become "small and somewhat solid (gel-like)" and become easier to degrade. This change can also be reversed by an enzyme called PP2A, making it a reversible change. In other words, it was found that p62 aggregates are not just "collections," but their properties (softness and size) determine how easily they are degraded.
Terminology
*1 Autophagy: A mechanism for degrading unnecessary substances and abnormal proteins in cells.
*2 p62: A protein that collects ubiquitinated proteins and guides them to degradation.
*3 Phosphorylation: A chemical modification that changes the function and properties of proteins.
*4 Ubiquitin: A marker molecule attached to proteins that should be degraded.
Researcher's Comment
This achievement involved a highly specialized technical staff member as the lead author, who was central to the meticulous research.