Class I PI3Ks activate stretch-induced autophagy in trabecular meshwork cells.

Area of Science:

• Ophthalmology
• Cell Biology
• Molecular Biology

Background:

• Elevated intraocular pressure (IOP) is a primary risk factor for glaucoma, a leading cause of irreversible blindness.
• IOP homeostasis depends on aqueous humor drainage via the trabecular meshwork (TM)/Schlemm's Canal (SC) pathway.
• Mechanical forces and primary cilia (PC)-dependent autophagy play a role in IOP homeostasis, but the upstream regulators are unclear.

Purpose of the Study:

• To investigate the upstream signaling pathway controlling autophagy activation during cyclic mechanical stretch (CMS) in human TM cells.
• To elucidate the molecular mechanisms underlying IOP homeostasis.

Main Methods:

• Biochemical and cell biological analyses of primary cultured human TM cells.
• Investigated the role of class IA, II, and III PI3Ks (phosphoinositide 3-kinases).
• Examined the localization of PIK3CA and the function of INPP4A/B (inositol polyphosphate-4-phosphatase).

Main Results:

• Human TM cells express class IA PI3K catalytic subunits (PIK3CA, PIK3CB, PIK3CD).
• Inhibition of class IA PI3Ks, but not class II or III, prevented CMS-induced autophagy.
• PIK3CA localized to primary cilia, and Class IA PI3Ks acted with INPP4A/B to regulate PI(3,4)P2 and PI(3)P levels, crucial for stretch-induced autophagy.

Conclusions:

• Class IA PI3Ks, in coordination with INPP4A/B, are key regulators of autophagy in response to mechanical stretch in TM cells.
• This pathway is critical for maintaining IOP homeostasis.
• Findings deepen the understanding of molecular mechanisms in IOP regulation and potential glaucoma therapeutic targets.