Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications

Abstract

Heat shock proteins (HSPs) of eukaryotes are evolutionarily conserved molecules present in all the major intracellular organelles. They mainly function as molecular chaperones and participate in maintenance of protein homeostasis in physiological state and under stressful conditions. Despite their relative abundance, the large HSPs, i.e., Hsp110 and glucose-regulated protein 170 (Grp170), have received less attention compared to other conventional HSPs. These proteins are distantly related to the Hsp70 and belong to Hsp70 superfamily. Increased sizes of Hsp110 and Grp170, due to the presence of a loop structure, result in their exceptional capability in binding to polypeptide substrates or non-protein ligands, such as pathogen-associated molecules. These interactions that occur in the extracellular environment during tissue injury or microbial infection may lead to amplification of an immune response engaging both innate and adaptive immune components. Here, we review the current advances in understanding these large HSPs as molecular chaperones in proteostasis control and immune modulation as well as their therapeutic implications in treatment of cancer and neurodegeneration. Given their unique immunoregulatory activities, we also discuss the emerging evidence of their potential involvement in inflammatory and immune-related diseases.

Honey Bee Pollen in Meagre (Argyrosomus regius) Juvenile Diets: Effects on Growth, Diet Digestibility, Intestinal Traits, and Biochemical Markers Related to Health and Stress

“…Members of the HSP70 family are widely used as biomarkers of environmental stress in ecological and toxicological studies in fish [36][37][38]. The functions of the different HSP70 family members depend on their cellular localization, acting both as chaperons and immunomodulators [38], with the general aim of maintaining protein homeostasis [39] in normal and stressful conditions. HSP70 can be induced in response to thermal stress, hypoxia, oxidative stress, ultraviolet radiation, nutrient deprivation, osmotic pressure, heavy metals, chemical agents, microbial infections, and inflammation [37][38][39][40][41].…”

Laser‐Triggered Small Interfering RNA Releasing Gold Nanoshells against Heat Shock Protein for Sensitized Photothermal Therapy

“…[8] Hsp70 has also been evidenced to exert antiapoptosis effects by inhibiting caspase-3 activation and blocking kinase pathways activated by cellular stresses. [9][10][11][12] These cytoprotective effects render tumor resistant to PTT induced apoptosis. Therefore, the inhibition of Hsp70, a recognized target in cancer treatment, may sensitize cancer cells to PTT.…”

“…Hsp70 has also been evidenced to exert antiapoptosis effects by inhibiting caspase‐3 activation and blocking kinase pathways activated by cellular stresses 9, 10, 11, 12. These cytoprotective effects render tumor resistant to PTT induced apoptosis.…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…HSPs are protein chaperones induced upon cellular stress, especially during states of injury and wound healing (Binder, 2014; Zuo et al, 2016). HSPs are known to participate in early TLR / NLR signaling and can even serve as TLR ligands.…”