Adding Some “Splice” to Stress Eating: Autophagy, ESCRT and Alternative Splicing Orchestrate the Cellular Stress Response

Abstract

Autophagy is a widely studied self-renewal pathway that is essential for degrading damaged cellular organelles or recycling biomolecules to maintain cellular homeostasis, particularly under cellular stress. This pathway initiates with formation of an autophagosome, which is a double-membrane structure that envelopes cytosolic components and fuses with a lysosome to facilitate degradation of the contents. The endosomal sorting complexes required for transport (ESCRT) proteins play an integral role in controlling autophagosome fusion events and disruption to this machinery leads to autophagosome accumulation. Given the central role of autophagy in maintaining cellular health, it is unsurprising that dysfunction of this process is associated with many human maladies including cancer and neurodegenerative diseases. The cell can also rapidly respond to cellular stress through alternative pre-mRNA splicing that enables adaptive changes to the cell’s proteome in response to stress. Thus, alternative pre-mRNA splicing of genes that are involved in autophagy adds another layer of complexity to the cell’s stress response. Consequently, the dysregulation of alternative splicing of genes associated with autophagy and ESCRT may also precipitate disease states by either reducing the ability of the cell to respond to stress or triggering a maladaptive response that is pathogenic. In this review, we summarize the diverse roles of the ESCRT machinery and alternative splicing in regulating autophagy and how their dysfunction can have implications for human disease.

The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy

“…The disruption of splicing can affect autophagy at multiple stages, including recognition of cargo (PRPF8 and ULK1 splicing), LC3 lipidation (U2AF1 and ATG7 splicing), autophagosome formation (SRSF1 and Bcl-x splicing), and as we demonstrate here, autophagosome-lysosome fusion [67][68][69] . The mis-splicing of genes in the ESCRT-III pathway in particular, CHMP2B and CHMP4B, are known to impact autophagy and play roles in the pathogenesis of cancer and neurological diseases 11,12,70 . Here we have identified a novel conserved role for PRP4K in regulating autophagosome-lysosome fusion via CHMP4B splicing, which has implications for understanding how inhibition or loss of splicing kinases may contribute to disease pathogenesis through impaired autophagy, including aggressive cancer phenotypes associated with loss of PRP4K 20 .…”

“…For example, the alternative and mis-splicing of autophagy genes has been shown to impact the initiation of autophagy, the recognition of cargo, and autophagosome maturation [4][5][6][7][8][9] . Genes encoding endosomal sorting complex required for transport (ESCRT) proteins are also involved in key autophagy events such as phagophore closure and autolysosome formation 10,11 , and mis-splicing of ESCRT genes underlies defects in autophagy that contribute to the pathogenesis of cancer, eye disease and several neurological disorders 12 .…”

Dysregulated RNA processing and metabolism: a new hallmark of ageing and provocation for cellular senescence

“…A unifying feature of most of these provocations for senescence is an aberrant response to different types of cellular stress. Eukaryotic cells have several mechanisms to deal with internal and external stresses, but one of the most important is alternative mRNA processing and metabolism [20][21][22][23]. This term refers to the collection of phenomena that happen to an RNA molecule from its transcription to its degradation, to ensure correct regulation of gene expression.…”

Alternative Splicing in Human Physiology and Disease

“…Thus, alternative splicing of genes that are involved in autophagy adds another layer of complexity to the cell stress response and, consequently, cancer. In the review by Habib et al, the diverse roles of alternative splicing in regulating autophagy and their impact on human disease are adequately summarized [ 14 ].…”