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The Pathogenic Impact of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy

ABSTRACT: RNA splicing and the ubiquitin system allow the functional proteome to adapt in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here we show that the deregulation of the spliceosome B complex caused by USP39 deficiency leads to a novel splicing profile characterized by the use of cryptic 5′splice sites. Importantly, disruptive variants evade mRNA surveillance pathways and are translated into topologically incorrect proteins. These cryptic isoforms disrupt proteostasis and activate the unfolded protein response, causing ER stress-induced cell death. Human cells respond to this proteotoxicity by enhancing ubiquitin-mediated proteolysis and ER-phagy. Our findings show how cell death triggered by cryptic splicing can be mitigated, and provide insight into the molecular pathogenesis of diseases such as retinitis pigmentosa.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Hela Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Marina Hoffmann

LAB HEAD: Ivan Dikic

PROVIDER: PXD041509 | Pride | 2024-09-26

REPOSITORIES: pride

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			Action	DRS
	20201116_MHO_CP_HeLa_Igg_unt_01.raw	Raw
	20201116_MHO_CP_HeLa_Igg_unt_02_201118163254.raw	Raw
	20201116_MHO_CP_HeLa_Igg_unt_03.raw	Raw
	20201116_MHO_CP_HeLa_USP10_unt_01.raw	Raw
	20201116_MHO_CP_HeLa_USP10_unt_02.raw	Raw

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