SKArred 2 death: neuroinflammatory breakdown of the hippocampus

Abstract

A multitude of cellular responses to intrinsic and extrinsic signals converge on macroautophagy/autophagy, a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome, particularly during starvation or stress. In addition to protein degradation, autophagy is deeply interconnected with unconventional protein secretion and polarized sorting at multiple levels within eukaryotic cells. Secretory autophagy (SA) has been recognized as a novel mechanism in which autophagosomes fuse with the plasma membrane and actively participate in the secretion of a series of cytosolic proteins, ranging from tissue remodeling factors to inflammatory molecules of the IL1 family. SA is partially controlled by the glucocorticoid-responsive, HSP90 co-chaperone FKBP5 and members of the SNARE proteins, SEC22B, SNAP23, SNAP29, STX3 and STX4. SA deregulation is implicated in several inflammatory pathologies, including cancer, cell death and degeneration. However, the key molecular mechanisms governing SA and its regulation remain elusive, as does its role in neuroinflammation and neurodegeneration. To further characterize SA and pinpoint its involvement in neuroinflammatory processes, we studied SA-relevant protein interaction networks in mouse brain, microglia and human postmortem brain tissue from control subjects and Alzheimer disease cases. We demonstrate that SA regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling.

Keywords: Alzheimer’s disease; FKBP5; SKA2; hippocampus; neuroinflammation; secretory autophagy.

Figure 1.

SKA2 acts as a molecular roadblock for autophagosome-plasma membrane fusion in secretory autophagy (SA), a non-lytic pathway utilizing autophagy proteins, chaperones, cargo receptors, and RQ-SNARE fusion proteins for vesicle secretion. SA is associated with neuroplasticity, extracellular matrix (ECM) remodeling, and immune responses as part of cellular homeostasis (left). The loss of SKA2 in the brain releases the brakes on SA, leading to hyperactivated, uncontrolled SA. This results in enhanced IL1B secretion, inflammasome activation, and neuroinflammation-induced neurodegeneration, implicating SA in the pathophysiology of Alzheimer disease (AD) (right). sm, sequestration membrane; sa, secretory autophagosome.