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Stress granules protect ER-exit sites from TDP43 aggregation

ABSTRACT: Aggregation of proteins under cellular stress plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and physiological consequences is poorly understood. We employed a general reporter to identify proteins forming aggregates under proteotoxic stress in human cells. Over 300 proteins were identified, forming different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule (SG) and a previously unknown solid inclusion containing components of the ER exit sites (ERES), such as SEC16A. TDP43 accumulation at ERES is antagonized by SG assembly, but enhanced by certain ALS-associated mutations. TDP43-ERES aggregation biases toward nascent TDP43 and, unlike SG, does not contain RNA. Such aggregation causes defects in ER-to-Golgi protein transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patient neurons.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Rong Li

PROVIDER: PXD041480 | JPOST Repository | Fri Apr 12 00:00:00 BST 2024

REPOSITORIES: jPOST

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Source:

			Action	DRS
	20190611_Human_UniProt.fasta	Fasta
	20210119_JW_HY_Agg_.msf	Msf
	20210119_JW_HY_Agg_.pdResult	Other
	20210119_JW_HY_Agg_14pc.raw	Raw
	20210119_JW_HY_Agg_24pc.raw	Raw

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Project description:Protein aggregation is a hallmark of many neurodegenerative diseases. In order to cope with misfolding and aggregation, cells have evolved an elaborate network of molecular chaperones, composed of different families. But while chaperoning mechanisms for different families are well established, functional and regulatory diversification within chaperone families is still largely a mystery. Here we decided to explore chaperone functional diversity, through the lens of pathological aggregation. We revealed that different naturally-occurring isoforms of DNAJ chaperones showed differential effects on different types of aggregates. We performed a chaperone screen for modulators of two neurodegeneration-related aggregating proteins, the Huntington’s disease-related HTT-polyQ, and the ALS-related mutant FUS (mutFUS). The screen identified known modulators of HTT-polyQ aggregation, confirming the validity of our approach. Surprisingly, modulators of mutFUS aggregation were completely different than those of HTT-polyQ. Interestingly, different naturally-occurring isoforms of DNAJ chaperones had opposing effects on HTT-polyQ vs. mutFUS aggregation. We identified a complex of the full length (FL) DNAJB14 and DNAJB12 isoforms which substantially alleviated mutFUS aggregation, in an HSP70-dependent manner. Their naturally occurring short isoforms were unable to form the complex, nor to interact with HSP70, and lost their ability to reduce mutFUS aggregation. In contrast, the short isoform of DNAJB12 significantly alleviated HTT-polyQ aggregation, while DNAJB12-FL aggravated HTT-polyQ aggregation. Finally, we demonstrated that full-length DNAJB14 ameliorated mutFUS aggregation compared to DNAJB14-short in primary neurons. Together, our data unraveled distinct molecular properties required for aggregation protection in different neurodegenerative diseases, and revealed a new layer of complexity of the chaperone network elicited by naturally occurring J-protein isoforms, highlighting functional diversity among the DNAJ family.

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Stress granules protect ER-exit sites from TDP43 aggregation

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