DDHD2 promotes lipid droplet catabolism by acting as a TAG lipase and a cargo receptor for lipophagy

ABSTRACT

Mutations in the DDHD2 (DDHD domain containing 2) gene cause autosomal recessive spastic paraplegia type 54 (SPG54), a rare neurodegenerative disorder characterized by the early childhood onset of progressive spastic paraplegia. DDHD2 is reported as the principal brain triacylglycerol (TAG) lipase whose dysfunction causes massive lipid droplet (LD) accumulation in the brains of SPG54 patients. However, the precise functions of DDHD2 in regulating LD catabolism are not yet fully understood. In a recent study, we demonstrate that DDHD2 interacts with multiple members of the Atg8-family proteins (MAP1LC3/LC3s, GABARAPs), which play crucial roles in lipophagy. DDHD2 possesses two LC3-interacting region (LIR) motifs that contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a compound that tethers LC3 to LDs to enhance their macroautophagic/autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide insights into the dual functions of DDHD2 as a TAG lipase and cargo receptor for lipophagy in neuronal LD catabolism, and also suggest a potential therapeutic approach for treating SPG54 patients.

KEYWORDS:

• Atg8
• hereditary spastic paraplegia
• LD·ATTEC
• lipid droplets
• lipophagy
• neurodegenerative disorders

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was in part supported by the National Natural Science Foundation of China (No. 92357301, 32370726, 81972396 to C.W., No. 82272992, 81872109 to K.G.), the State Key Development Programs of China (No. 2022YFA1104200 to C.W.), the Natural Science Foundation of Shanghai (No. 22ZR1449200 to K.G; 22ZR1406600 to C.W.), and the Open Research Fund of State Key Laboratory of Genetic Engineering, Fudan University (No. SKLGE-2111 to K.G), Open Research Fund of the Shanghai Key Laboratory of Maternal and Fetal Medicine (mfmkf202204 to C.W), Science and Technology Research Program of Shanghai (No. 9DZ2282100).