heat shock proteins

**Definition and classification:** HSPs (stress proteins) are highly conserved chaperones named by molecular weight (kDa): small HSPs (e.g., HSP27, αB-crystallin), HSP40, HSP60 (chaperonin, mitochondrial), HSP70, HSP90, and HSP100. Many are constitutively expressed (housekeeping chaperones) and are further induced by stress.

**Regulation:** Stress causes protein misfolding/denaturation. Misfolded proteins titrate HSP70/HSP90 away from heat shock factor 1 (HSF1). Free HSF1 trimerizes, translocates to the nucleus, and binds heat shock elements (HSE) in promoters, driving HSP gene transcription. This is a negative-feedback loop: as HSPs accumulate and refold proteins, they rebind HSF1 and shut off the response.

**Functions:** - Chaperoning: help nascent polypeptides fold properly (ATP-dependent; HSP70 binds exposed hydrophobic regions, HSP60 chaperonin provides a folding chamber). - Refolding of denatured proteins and preventing aggregation. - Targeting terminally misfolded proteins for ubiquitin-proteasome degradation (e.g., via CHIP, an E3 ligase interacting with HSP70/90). If damage is severe, can promote apoptosis. - Protein transport across membranes (mitochondria, ER). - HSP90 stabilizes steroid hormone receptors (glucocorticoid receptor) in an inactive cytoplasmic state until ligand binding, and also stabilizes client kinases (e.g., HER2, BCR-ABL, BRAF). - Ubiquitin: itself a stress-induced protein. - Related: Hsp47 for collagen; αB-crystallin in lens; cardioprotection/ischemic preconditioning.

**Clinical associations:** - **Cell injury:** Part of the reversible-injury response; HSPs and ubiquitin may accumulate when proteins are misfolded. Heat shock response is a classic cell-stress adaptation. Protein misfolding (e.g., Alzheimer, Parkinson, Huntington; prion disease) overwhelms chaperone capacity. - **Cancer:** HSP90 and HSP70 are overexpressed in many tumors, stabilizing mutant oncoproteins and promoting survival. HSP90 inhibitors (geldanamycin, 17-AAG) investigated as antineoplastics. - **Autoimmunity/infection:** Bacterial HSP60 (GroEL) shares homology with human HSP60, so molecular mimicry may contribute to autoimmunity (e.g., rheumatic fever, atherosclerosis, type 1 DM hypotheses). Extracellular HSPs act as danger signals via TLR2/TLR4 and can serve as antigen carriers for cross-presentation. - **Genetic disease:** Mutations in small HSPs and chaperonins cause neuropathies and myopathies (e.g., HSPB1/HSPB8 → Charcot-Marie-Tooth/distal hereditary motor neuropathy; αB-crystallin mutation → cataract and desmin-related myopathy; HSP60 mutations → hereditary spastic paraplegia, SPG13). Chaperonin CCT/TRiC mutations also reported. - **Heat illness:** HSP induction (thermotolerance) underlies acclimatization to heat; heat stroke involves overwhelmed protective responses and multiorgan injury. - **Ischemia:** HSP induction contributes to ischemic preconditioning, protecting myocardium.

**High-yield pearls for boards:** 1. HSPs = chaperones induced by stress (heat, hypoxia, toxins, free radicals). 2. They refold damaged proteins; if refolding fails, ubiquitin tags them for proteasomal degradation. 3. Misfolded protein accumulation in the ER → unfolded protein response (UPR) (related but distinct; involves BiP/GRP78, an HSP70 family member). 4. HSF1 is the transcription factor. 5. HSP90 holds steroid receptors inactive. 6. Bacterial HSP60 mimicry → autoimmunity concept. 7. Do not confuse with cold shock proteins or with acute phase reactants.