IRAK family proteins play critical roles in regulating innate immunity. There are three differentially spliced variants of IRAK1, namely 1, 1b, and 1c. We and others have previously identified that the full length IRAK1 underwent covalent modifications such as phosphorylation and ubiquitination upon lipopolysaccharide challenge. In this report, we observed that IRAK1 could also undergo sumoylation which was responsible for its translocation into the nucleus. In contrast, IRAK1c remained stable and did not undergo modification upon various challenges. Furthermore, we showed that IRAK1c solely localized in the cytoplasm. IRAK1 was absent and IRAK1c was the primary form in human brains. The absence of full length IRAK1 and presence of IRAK1c may keep brain tissue in a resting non-inflammatory state. Intriguingly, the full length IRAK1 form was consistently detected in brain tissues obtained from aged humans, suggesting that differential splicing of IRAK1 may correlate with the aging process.