Metabolic and Chaperone Gene Loss Marks the Origin of Animals: Evidence for Hsp104 and Hsp78 Chaperones Sharing Mitochondrial Enzymes as Clients

Abstract

The evolution of animals involved acquisition of an emergent gene repertoire for gastrulation. Whether loss of genes also co-evolved with this developmental reprogramming has not yet been addressed. Here, we identify twenty-four genetic functions that are retained in fungi and choanoflagellates but undetectable in animals. These lost genes encode: (i) sixteen distinct biosynthetic functions; (ii) the two ancestral eukaryotic ClpB disaggregases, Hsp78 and Hsp104, which function in the mitochondria and cytosol, respectively; and (iii) six other assorted functions. We present computational and experimental data that are consistent with a joint function for the differentially localized ClpB disaggregases, and with the possibility of a shared client/chaperone relationship between the mitochondrial Fe/S homoaconitase encoded by the lost LYS4 gene and the two ClpBs. Our analyses lead to the hypothesis that the evolution of gastrulation-based multicellularity in animals led to efficient extraction of nutrients from dietary sources, loss of natural selection for maintenance of energetically expensive biosynthetic pathways, and subsequent loss of their attendant ClpB chaperones.

A screen for gene paralogies delineating evolutionary branching order of early Metazoa

“…6) to a transition from a holopelagic to a biphasic pelago-benthic life cycle in the stem-benthozoan lineage. This particular result furthers a growing picture of metabolic and chaperone gene loss and gene innovation in early animal evolution (ERIVES AND FASSLER 2015;RICHTER et al 2018).…”

Mechanistic and Structural Insights into the Prion-Disaggregase Activity of Hsp104

“…Potentiating mutations enable Hsp104 to dissolve fibrils formed by human neurodegenerative disease proteins such as TDP-43, FUS, and α-synuclein, and mitigate neurodegeneration under conditions where wild-type (WT) Hsp104 is inactive [7]. Intriguingly, Hsp104 is absent from metazoa, but is found in all other eukaryotes as well as all eubacteria and some archaebacteria [42-45]. It has only recently been appreciated that metazoa rely upon the Hsp110, Hsp70, and Hsp40 chaperone system to disaggregate and reactivate proteins [5, 14, 46-51].…”

Designer protein disaggregases to counter neurodegenerative disease

“…Intriguingly, Hsp104 is absent from metazoa, but is found in all non-metazoan eukaryotes, all eubacteria, and some archaebacteria [45]. Thus, Hsp104 could be developed into a vital disruptive technology that retools proteostasis to combat neurodegenerative disease and HIV infection [28,43••,46].…”

“…Bafflingly, Hsp104 is absent from metazoa [28,45], and whether metazoa even possess a protein disaggregation and reactivation machinery had endured as a long-standing enigma [41,52]. It is now clear that human Hsp110, Hsp70, and Hsp40 synergize to dissolve and reactivate model proteins trapped in disordered aggregates and depolymerize amyloid fibrils formed by α-syn [41,52,76–80].…”