Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy.
• Posttranslational modifications are increasingly recognized as critical regulators of TFEB activity.

Purpose of the Study:

• To investigate the role of lactate in TFEB regulation.
• To elucidate the mechanism by which lactate affects TFEB activity and autophagy.
• To explore the clinical relevance of TFEB lactylation in cancer.

Main Methods:

• In vitro assays to demonstrate TFEB lactylation.
• Ubiquitination and proteasome degradation assays.
• Immunohistochemistry using a specific antibody for lactylated TFEB (K91).

Main Results:

• Lactate covalently modifies TFEB, resulting in lactylation at K91.
• Lactylation at K91 inhibits TFEB interaction with WWP2, preventing ubiquitination and degradation.
• Lactylated TFEB exhibits increased activity, leading to enhanced autophagy flux.
• Elevated TFEB lactylation is detected in human pancreatic cancer tissues.

Conclusions:

• Lactylation represents a novel posttranslational modification regulating TFEB.
• Lactylation stabilizes TFEB by preventing its degradation, thereby enhancing autophagy.
• TFEB lactylation is associated with high autophagy levels in proliferating cancer cells.