Biology subjects

Chase, K. J.

Publications and source records attributed to Chase, K. J..

3 recordsLinked to original sources

bioRxiv2026

Reconstructing a Missing Link of HIV-1 Assembly: HIV-1 Envelope-Matrix Interactions in a Native Viral Context

The envelope surface glycoprotein (Env) on HIV-1 drives cell entry and genome delivery through its receptor binding and membrane fusion activities. Incorporation of Env onto assembling virions is governed by its cytoplasmic tail (Env-CT) and the matrix (MA) domain of the PR55Gag (Gag) polyprotein. To better understand how Gag recruits Env onto virions while reducing its antigenic profile by restricting Env copy number to low levels, we used cryo-electron tomography (cryo-ET) and subtomogram averaging combined with molecular dynamics simulations to investigate Env-MA association in intact viral particles. Full-length Env-CT was resolved directly over individual MA trimers in regions of MA lattice discontinuity. We observed that the conserved but enigmatic Kennedy-sequence motif in Env-CT forms a key linkage between Env and MA. Mutational analysis confirmed the impact of specific CT and MA interactions on Env incorporation. Gag maturation released MA lattice restraints on Env, facilitating its clustering and promoting fusion activity.

biochemistry↗

bioRxiv2026

Structure of HIV-1 Env glycoprotein on virions reveals an alternative fusion subunit organization and native membrane coupling

An effective vaccine for Human Immunodeficiency Virus type-1 (HIV-1) has yet to be developed, and detailed characterization of functional Env glycoprotein, the primary antigenic target on virions, has remained elusive. While engineered Env trimers recapitulate many aspects of functional Env, key differences in antigenicity and dynamic behavior have been reported. Here, cryo-electron tomography and subtomogram averaging of HIV-1 virus-like particles (VLPs) revealed conformational differences in critical membrane-proximal regions compared to soluble Envs. Hydrogen/Deuterium-Exchange Mass Spectrometry and Molecular Dynamics captured dynamic profiles of membrane-bound Env and identified critical interactions with membrane. We show that disruption of the viral membrane results in relaxation of Env to a form that resembles engineered, soluble trimers. Additionally, Env from mature and immature VLPs exhibit only minor conformational differences, while surface clustering on virions changes significantly. These studies provide new insights into the essential role the membrane plays in maintaining Env in its native conformational form.

biochemistry↗

bioRxiv2022

C-Jun N-terminal Kinase Promotes Stress Granule Assembly and Neurodegeneration in C9orf72-mediated ALS and FTD

Stress granules (SGs), RNA/protein condensates assembled in cells under stress, are believed to play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, how SG assembly is regulated and related to pathomechanism is incompletely understood. Here, we show that ER stress activates JNK via IRE1 in fly and cellular models of C9orf72-mediated ALS/FTD (c9ALS/FTD), the most common genetic form of ALS/FTD. Furthermore, activated JNK promotes SG assembly induced by poly(GR) and poly(PR), two toxic proteins implicated in c9ALS/FTD, by promoting the transcription of G3BP1, a key SG protein. Consistent with these findings, JNK or IRE1 inhibition reduced SG formation, G3BP1 mRNA and protein levels, and neurotoxicity in cells overexpressing poly(GR) and poly(PR) or neurons derived from c9ALS/FTD patient induced pluripotent stem cells (iPSCs). Our findings connect ER stress, JNK, and SG assembly in a unified pathway contributing to c9ALS/FTD neurodegeneration.

neuroscience↗