Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin

Abstract

Amyloidogenic ‘gain-of-function' mutations in apolipoprotein A-I (ApoA-I) gene (APOA1) result in systemic amyloidosis characterized by aggregate deposition and eventually cell death. However, how amyloidogenic variants of ApoA-I induce cell death is unknown. Here we report that one of the mechanisms by which amyloidogenic ApoA-I induces cell death is through attenuating anti-stress activity of angiogenin (ANG), a homeostatic protein having both pro-growth and pro-survival functions. Under growth conditions, ANG is located in nucleolus where it promotes ribosomal RNA (rRNA) transcription thereby stimulating cell growth. In adverse conditions, ANG is relocated to cytoplasm to promote damage repairs and cell survival. We find that in cells overexpressing the L75P-APOA1 mutant ANG expression is decreased and normal cellular localization of ANG is altered in response to stress and growth signals. In particular, ANG does not relocate to cytoplasm under stress conditions but is rather retained in the nucleolus where it continues promoting rRNA transcription, thus imposing a ribotoxic effect while simultaneously compromising its pro-survival activity. Consistently, we also find that addition of exogenous ANG protects cells from L75P-ApoA-I-induced apoptosis.

Autophagy Alteration in ApoA-I Related Systemic Amyloidosis

“…We previously demonstrated that L75P-ApoA-I transfectants are more sensitive than control cells to serum withdrawal and hypothesized that cell death occurred via apoptosis [ 19 ]. To confirm this hypothesis, we analysed signs of apoptosis in HepG2 cells expressing the amyloidogenic variant L75P-ApoA-I.…”

“…We previously reported that, in L75P-ApoA-I transfectants, the amyloidogenic variant is retained within the cell, representing a stress factor [ 19 ]. Thus, we indirectly analysed the redox status of L75P-ApoA-I expressing cells by immunoblotting analysis of serine/threonine kinase protein kinase B (best known as AKT), MAP kinase p38 (MAPK) and the stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK) ( Figure 1 D–I).…”

“…The cDNA encoding this fibrillogenic variant has been previously utilized to stably transfect human liver cells. As hepatocytes express endogenous WT-ApoA-I, cells transfected with L75P-ApoA-I simultaneously express both the native protein and the L75P variant, presumably mimicking the heterozygous genotype of human patients [ 19 ].…”

Apolipoprotein A‐I: the dual face of a protein

“…In AApoAI patients, ApoAI and HDL plasma levels are generally lower than in normal subjects , although this seems not to be the cause of cardiovascular diseases . ApoAI‐decreased plasma levels may be related to the lower amount of secreted amyloidogenic variants with respect to wild‐type ApoAI, as demonstrated for L75P‐AApoAI overexpressed in stably transfected human hepatic cells , as well as for L75P‐ and L174S‐AApoAI variants in transiently transfected COS‐7 cells .…”

ApoA-I/HDL Generation and Intracellular Cholesterol Transport through Cytosolic Lipid-Protein Particles in Astrocytes

“…Haploinsufficiency of angiogenin, furthermore, is a risk factor of Alzheimer's disease. Amyloidogenic variant of apoA-I apparently induces cell death through reducing angiogenin expression to attenuate antistress activity [ 47 ]. These findings suggest that apoA-I not only has a role to regulate cholesterol homeostasis in the brain but also protects the brain from injury and stress.…”