Biology subjects

Nemec, A. A.

Publications and source records attributed to Nemec, A. A..

2 recordsLinked to original sources

bioRxiv2026

The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP

The multifunctional AAA+ ATPase p97/VCP is a pivotal regulator of cellular proteostasis, extracting polyubiquitinated substrates from protein complexes or organelle membranes for proteasomal degradation. Mutations in p97 are linked to a broad spectrum of neurodegenerative disorders, including multisystem proteinopathy and amyotrophic lateral sclerosis. Here, we provide insights into the basis of dysfunction in p97D395G, implicated in vacuolar tauopathy, using an integrated structural approach. The mutation destabilizes the interaction network in the transient ADP.Pi state previously identified in p97WT and alters the dynamics of the linker between the tandem ATPase domains, resulting in decreased ATPase activity. We further demonstrate that the D395G mutation sensitizes p97 to oxidative stress by enhancing C522 oxidation, thereby perturbing nucleotide binding in D2, and define the functional basis of this oxidative inactivation of p97. These findings reveal redox control as a key regulatory layer of the p97 ATPase cycle and provide a mechanistic framework for how oxidative stress contributes to p97-associated neurodegeneration.

molecular biology↗

bioRxiv2025

A microsporidial deubiquitinase blocks ubiquitin transfer from adenylated E1 to human UBE2K ubiquitin conjugating enzyme

Intracellular pathogens frequently subjugate the ubiquitin system to evade host immune defenses and establish intracellular replication niches. Microsporidia are obligate intracellular animal parasites that typically cause self-limiting infections in humans, but can sometimes cause fatal disseminated disease. At present, the ubiquitin system of microsporidia is virtually unexplored. Here, we discover a likely effector deubiquitinase (DUB) of the otubain subgroup from the human pathogenic microsporidian Encephalitozoon hellem, which we designate ehOTUB1. We find that ehOTUB1 selectively binds the human ubiquitin conjugating (E2) enzyme UBE2K and inhibits its ubiquitin conjugation activity independent of ehOTUB1 DUB activity. We show that ehOTUB1 obstructs docking of UBE2K onto ubiquitin E1 enzyme via steric conflict with ubiquitin in the E1 adenylation site to prevent ubiquitin transfer to UBE2K. This unconventional mechanism of E2 inhibition expands the known repertoire by which pathogens manipulate ubiquitin signaling, and suggests that direct inhibition of E2 enzymes may be a broader function of otubain subfamily DUBs than originally appreciated.

biochemistry↗