heat shock protein

**Function / Pathophysiology** - HSPs are molecular chaperones, constitutively expressed at baseline and induced by stress (hyperthermia, ischemia/hypoxia, free radicals, toxins, infection, heavy metals). - Induction: stress causes protein misfolding → misfolded proteins sequester HSPs away from HSF1 (heat shock factor 1) → HSF1 trimerizes, translocates to nucleus, binds heat shock elements (HSE) in promoters → increased HSP transcription (negative feedback when HSPs rebind HSF1). - Major families (named by kDa): - HSP70 (DnaK in bacteria): ATP-dependent; binds exposed hydrophobic regions of nascent/unfolded proteins to prevent aggregation. Works with HSP40 (J-protein) and nucleotide exchange factors. - HSP60 (GroEL/GroES, chaperonin): barrel-shaped chamber in mitochondria that refolds proteins in an isolated environment. - HSP90: stabilizes client proteins such as steroid hormone receptors (glucocorticoid, estrogen), kinases (e.g., BCR-ABL, HER2, BRAF, AKT), and p53 mutants; keeps receptors inactive until ligand binding. - Small HSPs (HSP27, αB-crystallin): prevent aggregation, stabilize cytoskeleton. - HSP104/ClpB (yeast/bacteria): disaggregase. - Link to ubiquitin: if refolding fails, co-chaperone CHIP (an E3 ligase) ubiquitinates substrate → proteasomal degradation. If damage is overwhelming, can contribute to apoptosis.

**Clinical significance / High-yield associations** - Cytoprotection: HSP induction underlies "ischemic preconditioning" and thermotolerance. - Cancer: HSP90 and HSP70 are overexpressed, helping stabilize mutant oncoproteins → HSP90 inhibitors (e.g., geldanamycin, 17-AAG) investigated as anti-cancer agents. - Neurodegeneration: protein misfolding/aggregation diseases (Alzheimer, Parkinson, Huntington, prion disease) involve overwhelmed chaperone/proteasome systems. - Cataracts/myopathy: mutations in αB-crystallin (small HSP, CRYAB) → cataracts and desmin-related myopathy/cardiomyopathy. - Charcot-Marie-Tooth / distal hereditary motor neuropathy: mutations in small HSPs (HSPB1/HSP27, HSPB8). - Autoimmunity/atherosclerosis: HSP60 is highly conserved; molecular mimicry between bacterial (e.g., GroEL) and human HSP60 may contribute to autoimmune responses and atherosclerosis. Rheumatic fever-type mimicry discussions often involve conserved antigens. - Cystic fibrosis: misfolded CFTR ΔF508 is recognized by HSP70/HSP90 chaperones and degraded; correctors (e.g., lumacaftor, tezacaftor, elexacaftor) aid folding/trafficking. - Heat stroke/fever: HSP expression increases; fever also boosts immune function. - Immunology: extracellular HSPs can act as danger signals/DAMPs and carry antigenic peptides to MHC class I (cross-presentation); HSP–peptide complexes explored for vaccines. - Bacterial HSPs: Hsp65 in Mycobacterium is an immunodominant antigen.

**Board pearls** - Chaperones assist protein folding in the ER too (e.g., BiP/GRP78 is an HSP70 family member; calnexin/calreticulin are lectin chaperones) → unfolded protein response (UPR) when overwhelmed. - Stress-induced misfolding → HSP up-regulation is part of cellular adaptation; failure → apoptosis. - Cell injury: HSPs and ubiquitin are cellular stress-response proteins seen in reversible injury; ubiquitin-protein complexes can form inclusions (Mallory bodies, Lewy bodies, neurofibrillary tangles).