Nascent polypeptide-associated complex (NAC)

The nascent polypeptide-associated complex (NAC) is a highly conserved, heterodimeric protein complex composed of alpha (NACA) and beta (BTF3) subunits that associates with the ribosome. It serves as one of the first cytosolic factors to encounter emerging nascent polypeptide chains, functioning as both a molecular chaperone and a gatekeeper for protein targeting. By competing with the signal recognition particle (SRP) for ribosome binding, NAC prevents the mistargeting of non-secretory proteins to the endoplasmic reticulum, thereby maintaining cellular proteostasis (Wiedmann et al., 1994; UniProt P15866, Q13765). Beyond its cytoplasmic role, subunits of NAC—particularly alpha-NAC—can translocate to the nucleus where they function as transcriptional co-activators for factors such as c-Jun, influencing developmental and proliferative pathways. In clinical contexts, the NAC complex is increasingly recognized for its role in disease progression. In cancer, NAC subunits are frequently overexpressed, promoting tumor cell survival and resistance to apoptosis by facilitating the folding of oncogenic proteins (Zhang et al., 2015). Conversely, in neurodegenerative conditions like Alzheimer's disease, a decrease in NAC levels or activity has been linked to the accumulation of misfolded protein aggregates and neuronal toxicity (Pezet et al., 2018). While it is currently considered a challenging therapeutic target due to its fundamental role in protein synthesis, experimental strategies focusing on the inhibition of its overexpression in oncology or the stabilization of its function in neurodegeneration are active areas of research.

Other names

Nascent polypeptide-associated complex subunit alpha (NACA)Nascent polypeptide-associated complex subunit beta (BTF3)Basic transcription factor 3Alpha-NAC/Beta-NAC complexRibosome-associated chaperone NAC

The complex functions by binding to the ribosome near the polypeptide exit tunnel to shield nascent chains from premature interactions and ensure correct targeting to organelles. It also acts as a transcriptional co-activator in the nucleus to modulate gene expression related to cell proliferation and survival.