Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives.

Viruses are intracellular parasites that subvert the functions of their host cells to accomplish their infection cycle. The endoplasmic reticulum (ER)-residing chaperone proteins are central for the achievement of different steps of the viral cycle, from entry and replication to assembly and exit. The most abundant ER chaperones are GRP78 (78-kDa glucose-regulated protein), GRP94 (94-kDa glucose-regulated protein), the carbohydrate or lectin-like chaperones calnexin (CNX) and calreticulin (CRT), the protein disulfide isomerases (PDIs), and the DNAJ chaperones. This review will focus on the pleiotropic roles of ER chaperones during viral infection. We will cover their essential role in the folding and quality control of viral proteins, notably viral glycoproteins which play a major role in host cell infection. We will also describe how viruses co-opt ER chaperones at various steps of their infectious cycle but also in order to evade immune responses and avoid apoptosis. Finally, we will discuss the different molecules targeting these chaperones and the perspectives in the development of broad-spectrum antiviral drugs.

Heat-shock proteins: chaperoning DNA repair.

Cells are repeatedly exposed to environmental or endogenous stresses that can alter normal cell behavior and increase cell vulnerability. In order to ensure tissue integrity and function, cells cope with cellular injuries by adapting their metabolism, protecting essential intracellular constituents, inhibiting cell death signaling pathways and activating those devoted to damage repair. The molecular chaperones of the heat-shock protein (HSP) family are critical effectors of this adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling cascades and preserve the intracellular signaling pathways that are essential for cell survival. Most HSPs are rapidly overexpressed in response to cellular injuries including genotoxic stress. DNA damage can dramatically alter cell behavior and contribute to a number of diseases including developmental defects, neurodegenerative disorders, and cancer. Thus, the ability of cells to repair DNA damage is essential for preserving cell integrity. DNA damage activates a coordinated response that includes detecting DNA lesions before their transmission to daughter cells, blocking cell cycle progression and DNA replication and repairing the damage. Although the role of HSPs in proteins homeostasis and cell death, especially apoptosis has been widely reported, much less is known about their function in DNA repair. This review aims to present the role of HSPs in DNA repair signaling pathways.

Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease.

Intermediate (CD14++CD16+) monocytes have important pro-inflammatory and atherogenic features and are increased in patients with chronic kidney disease (CKD). The present study aims to elucidate the role of the uremic milieu and of platelet activation in monocyte differentiation. Monocyte subtypes were analyzed in CKD patients (n = 193) and healthy controls (n = 27). Blood from healthy controls (Ctrl; n = 8) and hemodialysis patients (HD; n = 8) was centrifuged, and plasma (pl) was exchanged between Ctrl and HD (Ctrlcells/HDpl and HDcells/Ctrlpl) or reconstituted as original (Ctrlsham and HDsham) and incubated for 24 h (T24). Monocyte differentiation and platelet aggregation to monocytes (MPA) was assessed by flow cytometry. Especially, a higher proportion of CD14++CD16+ monocytes was found in hemodialysis (HD) patients (p < 0.01). In plasma exchange experiments, Ctrl cells/HD pl T24 showed an increased percentage of CD14++CD16+ monocytes versus Ctrl sham (33.7% ± 15 vs. 15.7% ± 9.6; P < 0.005), comparable to the level of CD14++CD16+ monocytes in the HD sham condition. The percentage of CD14++CD16+ monocytes was lowered by suspending HD cells in Ctrl pl (18.4% ± 7.8 vs. 36.7% ± 15 in HD sham; P < 0.005) reaching the level of the Ctrl sham condition (15.7% ± 9.6). A mixture of uremic sulfates increased CD14++CD16+ monocytes compared to control (19.8 ± 9.6% vs. 15.8 ± 10.9%; P < 0.05), paralleled by a rise MPA. Blocking MPA by abciximab, a potential therapeutic strategy, or anti-CD62P did not inhibit differentiation towards the CD14++CD16+ monocytes. In conclusion, in the present cohort, CD14++CD16+ monocytes are especially increased in HD patients and this can at least in part be attributed to the presence of the uremic milieu, with uremic sulfates inducing a reversible shift towards pro-inflammatory CD14++CD16+ monocytes.