Yook, J. I. | Search bioRxiv

bioRxiv2026

Interaction between TREM2-Macrophages and Cutibacterium acnes Drives Altered Lipid Metabolism in Chronic Apical Periodontitis

Chronic periapical periodontitis (CAP), highly prevalent worldwide, has long been regarded as non-specific inflammation. Lipophilic Cutibacerium acnes (CA) persistence in host macrophages has emerged as the pathologic background of sarcoidosis and acne vulgaris. Here we report that intracellular persistence of CA in TREM2-macrophages plays a pathologic role in CAP. We observed persistent CA in macrophages in most CAP samples. Our CA clinical isolates persist in the cytosolic space of macrophages, retarding phagolysosomal degradation accompanied by NLRP3-dependent inflammatory response. Subcutaneous injection of those isolates in vivo recapitulates subcutaneous aggregation of CA-laden macrophages. By single cell RNA sequencing analysis of defined CAP samples, we found that CA in TREM2-macrophages drives exuberant lipid droplets formation, indicating that immune cells are potential lipid provider in CAP. Our observations elucidate the mechanistic link whereby TREM2-macrophages and altered lipid metabolism provide a lipid-rich niche for CA, contributing to the pathophysiology of CAP.

microbiology↗

bioRxiv2022

Emergence of glycogen synthase kinase-3 interaction domain enhances phosphorylation of SARS-CoV-2 nucleocapsid protein

A structural protein of SARS-CoV-2, nucleocapsid (N) protein is abundantly expressed during viral replication. The N protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3{beta} constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), commonly found in many endogenous GSK-3{beta} binding proteins, such as Axins, FRATs, WWOX and GSKIP. Indeed, N interacts with GSK-3{beta} similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. Unlike with endogenous GID proteins, the N interaction neither disturbs endogenous GSK-3 activity nor regulates subsequent canonical Wnt activity and the Snail-EMT program. Notably, N abundance in SARS-CoV-2 is incomparably high compared to other coronaviruses, such as 229E, OC43 and HKU1. Compared to other coronaviruses, N harbors a CDK1 primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3{beta}. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allows increased abundance and hyper-phosphorylation of N. Our observations suggest that the emergence of GID and mutations for increased phosphorylation in N may have contributed to the emergence of SARS-CoV-2 and evolution of variants, respectively. Further study, especially in a BSL3-equipped facility, is required to elucidate the functional importance of GID and N phosphorylation in SARS-CoV-2 and variants.

cell biology↗