Trougakos, I. P. | Search bioRxiv

bioRxiv2021

Clusterin in Alzheimer's disease: an amyloidogenic inhibitor of amyloid formation

Clusterin is a heterodimeric glycoprotein (- and {beta}-chain), which has been described as an extracellular molecular chaperone. In humans, clusterin is an amyloid associated protein, co-localizing with fibrillar deposits in several amyloidoses, including Alzheimers disease. To clarify its potential implication in amyloid formation, we located aggregation-prone regions within the sequence of clusterin -chain, via computational methods. We had peptide-analogues of each region chemically synthesized and experimentally demonstrated that all of them can form amyloid-like fibrils. We also provide evidence that the same peptide-analogues can inhibit amyloid-{beta} fibril formation. These findings elucidate parts of the molecular mechanism in which clusterin inhibits amyloid formation. At the same time, they hint that molecular chaperones with amyloidogenic properties might have a role in the regulation of amyloid formation, essentially acting as functional amyloids.

biophysics↗

bioRxiv2019

Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B

Infection of Arabidopsis thaliana by the ascomycete fungus Colletotrichum higginsianum is characterised by an early symptomless biotrophic phase followed by a destructive necrotrophic phase. The fungal genome contains 77 secondary metabolism-related biosynthetic gene clusters (BGCs), and their expression during the infection process is tightly regulated. Deleting CclA, a chromatin regulator involved in repression of some BGCs through H3K4 trimethylation, allowed overproduction of 3 families of terpenoids and isolation of 12 different molecules. These natural products were tested in combination with methyl jasmonate (MeJA), an elicitor of jasmonate responses, for their capacity to alter defence gene induction in Arabidopsis. Higginsianin B inhibited MeJA-triggered expression of the defence reporter VSP1p:GUS, suggesting it may block bioactive JA-Ile synthesis or signalling in planta. Using the JA-Ile sensor Jas9-VENUS, we found that higginsianin B, but not three other structurally-related molecules, suppressed JA-Ile signalling by preventing degradation of JAZ proteins, the repressors of JA responses. Higginsianin B likely blocks the 26S proteasome-dependent degradation of JAZ proteins because it inhibited chymotrypsin- and caspase-like protease activities. The inhibition of target degradation by higginsianin B also extended to auxin signalling, as higginsianin B treatment reduced IAA-dependent expression of DR5p:GUS. Overall, our data indicate that specific fungal secondary metabolites can act similarly to protein effectors to subvert plant immune and developmental responses.\n\nHighlightA diterpene secondary metabolite produced by a fungal pathogen suppresses plant jasmonate defense signalling by preventing the proteasomal degradation of JAZ repressor proteins.

plant biology↗