Biology subjects

Grice, G. L.

Publications and source records attributed to Grice, G. L..

3 recordsLinked to original sources

bioRxiv2026

Regulation of proteasome activation by a ubiquitin-independent feedback mechanism

The ubiquitin-proteasome system is the major pathway for selective protein degradation in eukaryotic cells. Some proteins are degraded by the proteasome without ubiquitination, but the prevalence and underlying mechanisms remain poorly understood. Here, we use pulsed-SILAC proteomics to systematically identify proteins undergoing ubiquitin-independent proteasomal degradation (UbInPD). We identify the paralogous proteasome activation factors ZFAND5 and ZFAND6 (ZFAND5/6) and show that ZFAND5 contains a ubiquitin-independent degron that can both promote its rapid turnover and allosterically activate the proteasome. These findings support a model in which proteasome activation and activator degradation are coupled through a ubiquitin-independent feedback mechanism. We further show that ZFAND5/6, together with the scaffold protein p62, restrain NF-{kappa}B activation in the TLR4 pathway. We link this regulation to the degradation of UBCH5c, an abundant E2 ubiquitin-conjugating enzyme that can initiate or prime ubiquitin chain synthesis. Our findings expand the known landscape of UbInPD and reveal unexpected links between proteasome activation, E2 enzyme regulation, and inflammatory signalling.

biochemistry↗

bioRxiv2024

ABHD11 mediated deglutarylation regulates the TCA cycle and T cell metabolism

Glutarate is an intermediate of amino acid catabolism and an important metabolite for reprogramming T cell immunity, exerting its effects by inhibition of histone demethylase enzymes or through glutarylation. However, how distinct glutarate modifications are regulated is unclear. Here, we uncover a deglutarylation pathway that couples amino acid catabolism to tricarboxylic acid (TCA) cycle function. By examining how glutarate can form conjugates with lipoate, an essential mitochondrial modification for the TCA cycle, we find that Alpha Beta Hydrolase Domain 11 (ABHD11) protects against the formation of glutaryl-lipoyl adducts. Mechanistically, ABHD11 acts as a thioesterase to selectively remove glutaryl adducts from lipoate, maintaining integrity of the TCA cycle. Functionally, ABHD11 influences the metabolic reprogramming of human T cells, increasing central memory T cell formation and attenuating oxidative phosphorylation. These results uncover ABHD11 as a selective deglutarylating enzyme and highlight that targeting ABHD11 offers a potential approach to metabolically reprogramme cytotoxic T cells.

cell biology↗

bioRxiv2020

A thermostable, closed, SARS-CoV-2 spike protein trimer.

The spike (S) protein of SARS-CoV-2 mediates receptor binding and cell entry and is the dominant target of the immune system. S exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor binding site, and subsequently from prefusion to postfusion conformations to mediate fusion of viral and cellular membranes. S protein derivatives are components of vaccine candidates and diagnostic assays, as well as tools for research into the biology and immunology of SARS-CoV-2. Here we have designed mutations in S which allow production of thermostable, crosslinked, S protein trimers that are trapped in the closed, pre-fusion, state. We have determined the structures of crosslinked and non-crosslinked proteins, identifying two distinct closed conformations of the S trimer. We demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. This protein has potential applications as a reagent for serology, virology and as an immunogen.

biochemistry↗