Recent insights into HSP70: proteostasis and beyond

Since the 1980s, 70 kDa heat shock proteins (HSP70s) have been recognized as central regulators of proteostasis, with diverse roles in cellular physiology and pathology. Recent research has significantly expanded our understanding of these molecular chaperones, revealing functions that extend beyond their classical roles in proteostasis. In this review, we integrate these emerging insights with foundational knowledge by outlining the biology of HSP70s, with particular emphasis on recent discoveries, such as new data on the substrate specificity and molecular dynamics of HSP70-client interactions. In addition, increasing evidence highlights their noncanonical anti-inflammatory properties, as well as other nonimmune functions, including the promotion of adipose tissue browning and the enhancement of angiogenesis through extracellular HSP70 activity. Finally, although HSP70s have long been known to regulate mRNA degradation in a transcript-specific manner, new findings demonstrate their ability to bind double-stranded RNA, further broadening their functional repertoire.