Microautophagy plays a critical role in lysosomal repair and promotes healthy aging

To grow old or not to grow old! How does aging affect organisms at the cellular level? What are the mechanisms that help cells survive self-injury and trauma? Lysosomes are very important cellular structures and contain damaged cellular components. It is important in digesting bacteria and pathogens and is known to maintain stability within cells and tissues. But can it be repaired, and if so, how?

In a study published this month, EMBO reportResearchers from Osaka University and Nara Prefectural University of Medicine have shown that damaged lysosomes are repaired by a mechanism called “microautophagy” and identified two key regulators of this process.

Microautophagy is one of the three major types of autophagy in most higher organisms. This is a regulated process in which cellular components that are no longer functional or needed are broken down. It is thought that it is involved in a defense mechanism collectively called the lysosomal damage response, but the details are unknown.

Lysosomes are frequently damaged and lysosomal dysfunction is associated with accelerated aging and shortened lifespan. In this study, the researchers set out to understand the repair mechanism. To identify novel regulators of the lysosomal damage response, they focused on a signaling pathway called the Hippo pathway, which controls multiple processes such as cell proliferation. They knocked down individual components of the Hippo pathway in human cells and observed whether the cells were able to respond to the induced lysosomal damage. This screen revealed that a protein called serine-threonine kinase 38 (STK38) is essential for the lysosomal damage response.

They then discovered that STK38 functions in conjunction with a protein complex called the endosomal sorting complex required for transport (ESCRT) machinery. This complex was previously known to be involved in lysosomal repair. “STK38 is important for recruiting the ‘vacuolar protein sorting 4’ (VPS4) protein to damaged lysosomes and disassembling the ESCRT machinery at the end of the repair process,” explained Monami Ogura, lead author of the study. do. They further discovered that lysosomal membrane repair by the ESCRT mechanism is mediated by microautophagy.

They also show that non-canonical lipidation of a subfamily of autophagy-related protein 8 (ATG8) molecules, an important autophagy protein known as gamma-aminobutyric acid receptor-associated protein (GABARAP), is required for this process. was also identified. Lipidation, the process by which ATG8 is modified by lipid expansion, is the main process involved in autophagy. In non-canonical lipidation, ATG8 is lipidated into single-membrane endolysosomes rather than the double-membrane phagophore seen in standard lipidation.

Researchers have shown that GABARAP is essential for the first step of the lysosomal repair process.

We showed that noncanonical lipidation of ATG8 is important for the initial recruitment of the ESCRT machinery to damaged lysosomes and subsequent repair. ”

Shuhei Nakamura, senior author

The research team showed that depletion of microautophagy regulators increases the proportion of senescent cells and shortens lifespan. C.Elegance. Both STK38 and GABARAP have evolutionarily conserved roles, indicating the importance of this pathway in maintaining lysosomal integrity, healthy cellular function, and preventing cellular and biological aging. The detailed understanding provided by this research paves the way to promoting healthy aging and has great therapeutic value in the treatment of age-related diseases.