The huntingtin-HAP40 complex is a bidirectional cellular rheostat

Abstract

Huntingtin-associated protein 40 (HAP40) is an obligate structural subunit of huntingtin (HTT) and is rapidly degraded when unbound, yet has been conserved across eukaryotes for over a billion years. Combining interactomics, quantitative respirometry, and transcriptomics, we show that the HTT-HAP40 complex functions as a bidirectional stoichiometric rheostat: unbuffered apo-HAP40 activates the Integrated Stress Response via ATF4 and DDIT3/CHOP, whereas unbuffered apo-HTT reciprocally drives cholesterol and fatty-acid biosynthesis through SREBF1/2. We identify the ER-mitochondria tether RMDN3 (PTPIP51) as a key HAP40 interactor, placing mitochondria-associated ER membranes (MAMs) at the rheostats convergence point, and demonstrate that HAP40 depletion specifically impairs respiratory complexes II/IV. Loss of rheostat balance reproduces transcriptional signatures of Huntingtons disease patient tissues, supporting a "dual failure" model in which collapse of stoichiometric buffering -- rather than aggregation toxicity alone -- drives pathogenesis. To our knowledge, this is the first obligate complex in which both unbound partners carry out distinct essential functions, defining stoichiometric buffering as a generalizable regulatory principle that couples complex assembly to metabolic and stress-response control across eukaryotes.