A team of researchers has unveiled a new mechanism that is vital for starting autophagy. The study emphasizes the importance of ZDHHC13, an enzyme that modifies ULK1 through palmitoylation, in activating autophagy. This finding provides insights into the molecular processes involved in autophagy and its relevance to diseases such as cancer, neurodegenerative disorders, and age-related ailments.
An international research team led by Osaka University has pinpointed a new mechanism that plays an essential role in initiating autophagy. This is a self-cleaning process that cells use to get rid of unnecessary or damaged parts. Lately, autophagy has garnered attention for its significance in regulating aging and lifespan.
During autophagy, various molecules and cell structures are enclosed within a membrane-bound vesicle known as an autophagosome, which is later broken down in lysosomes. It is well-established that the process of forming autophagosomes requires the coordinated effort of several proteins associated with autophagy.
Previously, this research group found that autophagosome formation occurs on the membranes of the endoplasmic reticulum, closely associated with mitochondria in cells. They also discovered that the PI3K complex, a protein involved in autophagy, is crucial for this formation process. The activity of this PI3K complex is regulated by the ULK1 complex.
The ULK1 complex is known to move from the cytoplasm to the endoplasmic reticulum membrane where it facilitates autophagosome formation at the beginning of autophagy. However, the precise mechanism and implications of this movement were not clearly understood until now. In a recent publication in Nature Communications, the research team disclosed that the palmitoylation of ULK1 leads to a cascade of events that kickstart autophagy.
By investigating the internal factors that contribute to the initiation of autophagy, the team identified ZDHHC13, an enzyme responsible for palmitoylation, as a crucial component in this process.
Mutations in ZDHHC13 have been associated with various diseases, including Huntington’s disease, while autophagy itself plays a significant role in the development and progression of illnesses such as cancer and neurodegenerative diseases.
Senior author Maho Hamasaki stated, “Our research revealed that ZDHHC13 palmitoylates ULK1, facilitating the localization of the ULK1 complex to the sites where autophagosomes are formed. This modification is also involved in the phosphorylation of the ATG14L protein within the PI3K complex, which in turn modulates the activity of the PI3K complex.”
Gaining an understanding of the molecular mechanisms that trigger autophagy is anticipated to improve our comprehension of diseases related to autophagy.
Lead author Keisuke Tabata remarked, “Autophagy not only supplies nutrients through the breakdown of internal components but also plays a vital role in ensuring normal cell functionality and preventing various diseases. We plan to continue exploring how autophagy is initiated, enhancing our understanding of the mechanisms behind related diseases.”
