White matter hyperintensity genetic risk factorTRIM47regulates autophagy in brain endothelial cells

Abstract

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Usingin silicosimulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencingTrim47significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.SUMMARY STATEMENTTRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.

TRIM44 Promotes Rabies Virus Replication by Autophagy-Dependent Mechanism

“…Studies have reported that TRIM44 not only participates in the innate immunity against viral infection [31] but also acts as a bridge between cellular autophagy and the ubiquitin-proteasome degradation system [24]. Similarly, TRIM47 is involved in the innate immunity against viral infection [32] and is associated with neuronal autophagy [33], while TRIM56 regulates replication of many viruses [34,35]. Therefore, we chose to explore TRIM44, TRIM47, and TRIM56, as these TRIM proteins' mechanisms in RABV infection have not been studied.…”