PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Mutations in the Plekhm1 gene cause osteopetrosis, a bone disease linked to impaired osteoclast function.
• PLEKHM1 is known to bind RAB7 and is crucial for lysosome trafficking, but its precise regulatory mechanisms are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which PLEKHM1 regulates lysosomal pathways and osteoclast function.
• To investigate the role of PLEKHM1 in lysosome positioning and bone resorption.

Main Methods:

• Generation of germline and conditional Plekhm1-deficient mice.
• Analysis of osteoclast function, lysosome distribution, and bone mass in knockout mice.
• Investigation of protein interactions between PLEKHM1, DEF8, FAM98A, NDEL1, and RAB7.

Main Results:

• Plekhm1-deficient mice exhibited increased trabecular bone mass and defective osteoclast bone resorption.
• Loss of PLEKHM1 disrupted the peripheral distribution of lysosomes in osteoclasts.
• DEF8, FAM98A, and NDEL1 were identified as interacting partners of PLEKHM1, linking lysosomes to RAB7 and microtubules, and their suppression mimicked Plekhm1-null phenotypes.

Conclusions:

• PLEKHM1, DEF8, FAM98A, and NDEL1 form a molecular complex essential for regulating lysosome positioning and secretion via RAB7.
• This complex is critical for normal osteoclast function and bone resorption, providing new insights into osteopetrosis pathogenesis.