414 | Nature | Vol 584 | 20 August 2020
Article
Thus, stress-activated MAPK signalling controls the upregulation of
extracellular proteostasis during a pathogenic attack.
Finally, we investigated whether enhanced extracellular proteo-
stasis confers a survival advantage against pathogens. Animals over-
expressing F56B6.6, CLEC-1 or LYS-3 were strongly protected against
lethality induced by Cry5B, with a more than 30% increase in viabil-
ity (Fig. 3f, Extended Data Table 2). By contrast, reduced expression
caused hypersensitivity. Similarly, RNAi targeting tag-196 and F54E2.1,
two ECRs strongly induced by Cry5B, as well as coelomocyte ablation
accelerated C. elegans demise on the toxin. LBP-2 or secreted GFP
overexpression alone did not negatively influence survival on Cry5B
(Extended Data Fig. 6f–i, Extended Data Tables 2, 3). To investigate
how enhanced extracellular proteostasis helps the host to survive an
initially localized pathogenic attack, we performed RNA sequencing
on Cry5B-challenged and -unchallenged animals. First, we found that
animals with enhanced extracellular proteostasis achieved a higher
upregulation of pathogen-response genes during exposure to Cry5B,
including genes such as collagens expressed in non-intestinal tissues.
Second, there is no evidence that ECR upregulation itself triggers an
immune response in basal conditions (Extended Data Fig. 7, Supple-
mentary Table 3). These results suggest that a healthy extracellular
proteome supports a transcriptional response to pathogens, in several
tissues, without inducing it. Also, extracellular aggregates are probably
a liability during the attack as increased extracellular protein aggre-
gation is associated with hypersensitivity to Cry5B (Extended Data
Fig. 6f, j). Optimizing extracellular proteostasis would sustain a sys-
temic immune response by ensuring favourable pseudocoelomic con-
ditions for intercellular signalling^22 and by keeping secreted immune
factors functional. CLEC-1 secreted from body-wall muscles was highly
effective in preventing aggregation of the immune factor LYS-7, which
is mainly produced by the intestine^15 (Extended Data Fig. 3e).
We have uncovered the extracellular proteostasis network that
regulates protein aggregation outside of the cell in C. elegans, prob-
ably through diverse mechanisms. Similar to the ER unfolded protein
response^9 ,^16 ,^23 , extracellular proteostasis has a role in ageing and in the
response to pathogens. We propose that induction of extracellular pro-
teostasis contributes to the host’s systemic defence to counter pathogen
propagation^24 from different sites of attack while alleviating proteotoxic-
ity from enhanced immunity-related secretion. Notably, bioinformatic
analysis revealed that half of the 57 ECRs have potential human ortho-
logues of which the majority are expressed in the brain and have associa-
tions with neurodegenerative diseases, including some differentially
regulated in cerebrospinal fluid from Alzheimer’s disease^25 (Supplemen-
tary Table 4). This orthologue list is likely to be a valuable source for the
discovery of human extracellular proteostasis components relevant for
Alzheimer’s disease. Strong evidence already supports the protective
role of extracellular proteostasis in Alzheimer’s disease, and both the
extracellular chaperone clusterin and the microglia receptor TREM2,
which act together to facilitate the removal of pathological amyloid-β,
are risk factors for Alzheimer’s disease^26 –^30. Moreover, knowledge of the
control over extracellular proteostasis in C. elegans can pave the way for
the discovery of a similar master regulator in mammals.
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